More Evidence of Link Between Severe Gum Disease and Cancer Risk

Data collected during a long-term health study provides additional evidence for a link between increased risk of cancer in individuals with advanced gum disease, according to a new collaborative study led by epidemiologists Dominique Michaud at Tufts University School of Medicine and Elizabeth Platz of the Johns Hopkins Bloomberg School of Public Health and Kimmel Cancer Center.

The study, published in the Journal of the National Cancer Institute, used data from comprehensive dental exams performed on 7,466 participants from Maryland, Minnesota, Mississippi, and North Carolina, as part of their participation in the Atherosclerosis Risk in Communities (ARIC) study who were then followed from the late 1990s until 2012. During the follow-up period, 1,648 new cancer cases were diagnosed.

The research team found a 24 percent increase in the risk of developing cancer among participants with severe periodontitis, compared to those with mild to no periodontitis at baseline. Among patients who had no teeth—which can be a sign of severe periodontitis—the increase in risk was 28 percent. The highest risk was observed in cases of lung cancer, followed by colorectal cancer.

When the researchers did sub-group analyses, they found that participants with severe periodontal disease had more than double the risk of developing lung cancer, compared with no/mild periodontitis. An 80 percent increase in risk of colon cancer observed for participants who were edentulous at baseline, which is consistent with prior findings, and among never smokers, a two-fold higher risk was noted for participants with severe periodontitis, compared to those who had no/mild periodontitis.

“This is the largest study addressing the association of gum disease and cancer risk using dental examinations to measure gum disease prior to cancer diagnosis,” said first and corresponding author Dominique Michaud, Sc.D., professor of public health and community medicine at Tufts University School of Medicine. “Additional research is needed to evaluate if periodontal disease prevention and treatment could help alleviate the incidence of cancer and reduce the number of deaths due to certain types of cancer.”

Michaud noted that the findings were particularly interesting in light of research, including a recent study in Science, which determined that colorectal cancer tissues contain bacteria that are present in the mouth, including bacteria that have been associated with periodontal disease.

The researchers also uncovered a small increase in the risk of pancreatic cancer in patients with severe periodontitis. Although not significant statistically, the association has been seen in other similar studies, including a number of studies led by Michaud of Tufts.

The research team accounted for the impact of smoking among the participants, since people who smoke are more likely to get periodontal disease, and smoking raises the risk of lung and colon cancers.

“When we looked at data for the people who had never smoked, we also found evidence that having severe periodontal disease was related to an increased risk of lung cancer and colorectal cancer,” said Elizabeth Platz, Sc.D., deputy chair of the department of epidemiology at the Johns Hopkins Bloomberg School of Public Health and co-leader of the Cancer Prevention and Control Program at the Johns Hopkins Kimmel Cancer Center.

The ARIC data were especially useful to study because unlike most previous research linking gum disease and cancer risk, periodontitis cases were determined from dental examinations performed as part of the ARIC study rather than participants’ self-reports of the disease. The dental exams provided detailed measurements of the depth of the pocket between the gum and tooth in several locations in the mouth. The ARIC data include both Caucasian and African-American participants.

The researchers found no links between increased risk of breast, prostate or blood/lymphatic cancer and periodontitis. The link between periodontitis and increased cancer risk was weaker or not apparent in African-American participants from the ARIC study, except in cases of lung and colorectal cancer. “Additional research is needed to understand cancer-site specific and racial differences in findings,” wrote the authors. The researchers caution that the study was limited in size for subgroup analyses, and less common cancers. The findings, however, suggest the need for further study.

Michaud and Platz said the study also points to the importance of expanding dental insurance to more individuals. “Knowing more about the risks that come about with periodontal disease might give more support to having dental insurance in the way that we should be offering health insurance to everyone,” Platz said.

Advanced gum disease, also called periodontitis, is caused by bacterial infection that damages the soft tissue and bone that support the teeth. Previous research has shown a link between periodontitis and increased cancer risk, although the mechanism connecting the two diseases is still uncertain.

Flipping the Switch: Dietary Fat, Changes in Fat Metabolism May Promote Prostate Cancer Metastasis

Prostate tumors tend to be what scientists call “indolent” – so slow-growing and self-contained that many affected men die with prostate cancer, not of it. But for the percentage of men whose prostate tumors metastasize, the disease is invariably fatal. In a set of papers out today in the journals Nature Genetics and Nature Communications, researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) shed new light on the genetic mechanisms that promote metastasis in the mouse model and also implicated the typical Western high-fat diet as a key environmental factor driving metastasis.

“Although it is widely postulated that a Western diet can promote prostate cancer progression, direct evidence supporting a strong association between dietary lipids and prostate cancer has been lacking,” said first author Ming Chen, PhD, a research fellow in the laboratory of Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC.

Epidemiological data links dietary fats (and obesity) to many types of cancer, and rates of cancer deaths from metastatic cancers including prostate cancer are much higher in the United States than in nations where lower fat diets are more common. While prostate cancer affects about ten percent of men in Asian nations, that rate climbs to about 40 percent when they immigrate to the U.S., mirroring the rates among the native born U.S. population. That points to an environmental culprit that may work in concert with genetic factors to drive this aggressive, fatal disease.

“The progression of cancer to the metastatic stage represents a pivotal event that influences patient outcomes and the therapeutic options available to patients,” said senior author Pandolfi. “Our data provide a strong genetic foundation for the mechanisms underlying metastatic progression, and we also demonstrated how environmental factors can boost these mechanisms to promote progression from primary to advanced metastatic cancer.”

The tumor suppressor gene PTEN is known to play a major role in prostate cancer; its partial loss occurs in up to 70 percent of primary prostate tumors. Its complete loss is linked to metastatic prostate disease, but animal studies suggest the loss of PTEN alone is not enough to trigger progression. Pandolfi and colleagues sought to identify an additional tumor suppressing gene or pathway that may work in concert with PTEN to drive metastasis.

Looking at recent genomic data, Pandolfi and colleagues noticed that another tumor suppressor gene, called PML, tended to be present in localized (non-metastatic) prostate tumors, but was absent in about a third of metastatic prostate tumors. Moreover, about 20 percent of metastatic prostate tumors lack both PML and PTEN.

When they compared the two types of tumor – the localized ones lacking only the PTEN gene versus the metastatic tumors lacking both genes – the researchers found that the metastatic tumors produced huge amounts of lipids, or fats. In tumors that lacked both PTEN and PML tumor suppressing genes, the cells’ fat-production machinery was running amok.

“It was as though we’d found the tumors’ lipogenic, or fat production, switch,” said Pandolfi. “The implication is, if there’s a switch, maybe there’s a drug with which we can block this switch and maybe we can prevent metastasis or even cure metastatic prostate cancer,” he added.

Such a drug already exists. Discovered in 2009, a molecule named “fatostatin” is currently being investigated for the treatment of obesity. Pandolfi and colleagues tested the molecule in lab mice. “The obesity drug blocked the lipogenesis fantastically and the tumors regressed and didn’t metastasize.”

In addition to opening the door to new treatment for metastatic prostate cancer, these findings also helped solve a long-standing scientific puzzle. For years, researchers had difficulty modeling metastatic prostate cancer in mice, making it hard to study the disease in the lab. Some speculated that mice simply weren’t a good model for this particular disease. But the lipid production finding raised a question in Pandolfi’s mind.

“I asked, ‘What do our mice eat?’” Pandolfi recalled.

It turned out, the mice ate a vegetable-based chow – essentially a low-fat vegan diet that bore little resemblance to that of the average American male. When Pandolfi and colleagues increased the levels of saturated fats – the kind found in fast food cheeseburgers and fries – in the animals’ diet, the mice developed aggressive, metastatic tumors.

The findings could result in more accurate and predictive mouse models for metastatic prostate cancer, which in turn could accelerate discovery of better therapies for the disease. Additionally, physicians could soon be able to screen their early-stage prostate cancer patients for those whose tumors lack both PTEN and PML tumor suppressing genes, putting them at increased risk for progressing to metastatic disease. These patients may be helped by starving these tumors of fat either with the fat-blocking drug or through diet.

“The data are tremendously actionable, and they surely will convince you to change your lifestyle,” Pandolfi said.

Photographed: Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC

New Polygenic Hazard Score Predicts When Men Develop Prostate Cancer

An international team, led by researchers at the University of California San Diego School of Medicine, has developed and validated a genetic tool for predicting age of onset of aggressive prostate cancer, a disease that kills more than 26,000 American men annually.

The tool, described in the January 11 online issue of the BMJ (formerly the British Medical Journal), may potentially be used to help guide decisions about who to screen for prostate cancer and at what age.

Currently, detection of prostate cancer relies primarily upon the prostate-specific antigen (PSA) screening blood test. But PSA testing is not very good as a screening tool. While it reduces deaths from prostate cancer, indiscriminate PSA screening also produces false positive results and encourages over-detection of non-aggressive, slow-growing tumors.

“The existing PSA test is useful, but it is not precise enough to be used indiscriminately on all men,” said the study’s first author, Tyler M. Seibert, MD, PhD, chief resident physician in the Department of Radiation Medicine and Applied Sciences at UC San Diego School of Medicine. “As a result, it may prompt medical interventions like biopsy, surgery or radiotherapy that might not be necessary.”

Seibert, senior author Anders Dale, PhD, professor and co-director of the Center for Translational Imaging and Precision Medicine at UC San Diego School of Medicine, and colleagues in Europe, Australia and the United States, used genome-wide association studies (GWAS) to determine whether a man’s genetic predisposition to developing prostate cancer could be used to predict his risk of developing the aggressive and lethal form of the disease.

GWAS search individual genomes for small variations, called single-nucleotide polymorphisms (SNPs), that occur more frequently in people with a particular disease than in people without the disease. Hundreds or thousands of SNPs can be evaluated at the same time in large groups of people. In this case, researchers used data from over 200,000 SNPs from 31,747 men of European ancestry participating in the ongoing international PRACTICAL consortium project.

Using a method developed at UC San Diego, the researchers combined information from GWAS and epidemiological surveys to assess quantification for genetic risk at age of disease onset. “Polygenic Hazard Score methodology is specialized in finding age-dependent genetic risks and has already been proven to be very useful in predicting age of onset for Alzheimer’s disease”, said study co-author Chun Chieh Fan, MD, PhD, in the Department of Cognitive Science at UC San Diego.

“The polygenic hazard score is very versatile and can be applied to many age-related diseases,” said Fan. “In this case, the polygenic hazard score of prostate cancer captures the age variations of aggressive prostate cancer.”

Genotype, prostate cancer status and age were analyzed to select SNPs associated with prostate cancer diagnosis. Then the data was incorporated into the polygenic hazard score, which involves survival analysis to estimate SNPs’ effects on age at diagnosis of aggressive prostate cancer. The results led to a polygenic hazard score for prostate cancer that can estimate individual genetic risk. This score was then tested against an independent dataset, from the recent UK ProtecT trial, for validation.

“The polygenic hazard score was calculated from 54 SNPs and proved to be a highly significant predictor of age at diagnosis of aggressive prostate cancer,” said Seibert. “When men in the ProtecT dataset with a high polygenic hazard score were compared to those with average PHS, their risk of aggressive prostate cancer was at least 2.9 times greater.”

“And when we account statistically for the effect of the GWAS having disproportionately high numbers of men with disease compared to the general population, we estimate that the risk defined by the polygenic hazard score is 4.6 times greater.”

The study authors note that an individual’s genotype does not change with age, so the polygenic hazard score can be calculated at any time and used as a tool for men deciding whether and when to undergo screening for prostate cancer. This is especially critical for men at risk of developing prostate cancer at a very young age, before standard guidelines recommend consideration of screening.

“This kind of genetic risk stratification is a step toward individualized medicine,” said Dale, who also noted that PSA tests are much more predictive of aggressive prostate cancer in men with high polygenic hazard score than in those with low polygenic hazard score. This suggests that polygenic hazard score can help physicians determine whether to order a PSA test for a given patient, in the context of the patient’s general health and other risk factors.

Investigators caution that further study of the clinical benefits are needed before the polygenic hazard score is ready for routine use.

Texas A&M Research Shows Biological Clocks Could Improve Brain Cancer Treatment

Biological clocks throughout the body play a major role in human health and performance, from sleep and energy use to how food is metabolized and even stroke severity. Now, Texas A&M University researchers found that circadian rhythms could hold the key to novel therapies for glioblastoma, the most prevalent type of brain cancer in adults—and one with a grim prognosis.

Scientists in the Texas A&M Center for Biological Clocks Research (CBCR) determined that the timed production of a particular protein, associated with tumor proliferation and growth, is disrupted in glioblastoma cells, and they believe that this may lead to a more effective technique to treat the cancerous cells without damaging the healthy surrounding tissue. These findings, which were supported in part by the National Institutes of Health, were published today (Jan. 10) in the international journal BMC Cancer.

Texas A&M biologist Deborah Bell-Pedersen, PhD, a co-corresponding author on the study, found in her previous research that the biological clock in the model fungal system Neurospora crassa controls daily rhythms in the activity of a signaling molecule, called p38 mitogen activated protein kinase (MAPK). This signaling protein plays a role in glioblastoma’s highly invasive and aggressive properties.

In the new research, David J. Earnest, PhD, a mammalian biological clocks expert at the Texas A&M College of Medicine and co-corresponding author on the study, collaborated with Bell-Pedersen to show that the clock controls daily rhythms in p38 MAPK activity in a variety of mammalian cells as well, including normal glial cells, the supporting “helper” cells surrounding neurons.

Furthermore, their work found that such regulation is absent in glioblastoma cells. “We tested to see if inhibition of this cancer-promoting protein in glioblastoma cells would alter their invasive properties,” said Bell-Pedersen, an internationally recognized leader in the fields of circadian and fungal biology. “Indeed, we found that inhibition of p38 MAPK at specific times of the day—times when the activity is low in normal glial cells under control of the circadian clock—significantly reduced glioblastoma cell invasiveness to the level of noninvasive glioma cells.”

These findings indicate that glioblastoma might be a good candidate for chronochemotherapy, meaning treating cancer at specific times of day to get the most impact.

“Chronotherapeutic strategies have had a significant positive impact on the treatment of many types of cancer by optimizing the specific timing of drug administration to improve the efficacy and reduce the toxicity of chemotherapy,” Bell-Pedersen said. “However, circadian biology has not been applied to the development of chronotherapeutic strategies for the treatment of glioblastoma, and clinical outcomes for this common primary brain tumor have shown limited improvement over the past 30 years.”

Glioblastomas gained some attention this summer when Senator John McCain was diagnosed with the condition. “A big reason for poor prognosis for patients with this aggressive type of tumor is that the glioblastoma cells rapidly and unabatedly invade and disrupt the surrounding brain cells,” said Gerard Toussaint, MD, a clinician and assistant professor at the Texas A&M College of Medicine who specializes in glioblastoma. Current treatments—including chemotherapy, surgical resection, immunotherapy and radiation—are largely ineffective in prolonging life expectancy beyond 18 months.

“We found that an inhibitor of p38 MAPK activity would make the cells behave less invasively, and if you can control the invasive properties, you can improve prognosis,” Earnest said. In addition, the team’s data indicate such treatment may be more effective and less toxic if administered at the appropriate time of the day.

This reduced toxicity is important, because a drug to inhibit the cancer-promoting activity of this protein was tested but found to be too harmful, with too many side effects. “If treatment with the drug can be timed to when the normal glial cells naturally have low activity of p38 MAPK, the addition of the drug might not be as toxic for these cells, and yet would still be very effective on the cancerous cells,” Earnest said.

Although promising, the current studies were done using cell cultures. The team’s next step is to test p38 inhibitor chronochemotherapy in an animal model for glioblastoma. If successful, they would then move on to clinical trials.

“We work on a model system, and the reason to do that is that we can make progress quickly, and we always hope that what we’re working on will lead to something useful, and I think this is a prime example of how putting effort into basic research can pay off,” Bell-Pedersen said. “We’re very hopeful and encouraged by our data that we’ll find a treatment.”

BriaCell Provides Clinical Update on its Lead Immunotherapy Drug in Advanced Breast Cancer

BriaCell, an immuno-oncology focused biotechnology company with a proprietary targeted immunotherapy technology, has provided a clinical update regarding its ongoing clinical trials of Bria-IMT™ (formerly referred to as SV-BR-1-GM).

BriaCell currently is enrolling patients in two separate but related clinical trials. Trial WRI-GEV-007 (listed in ClinicalTrials.gov as NCT03066947) is a Phase I/IIa clinical study designed to evaluate the safety and efficacy of Bria-IMT™ in metastatic or locally recurrent breast cancer patients.  In this study, Bria-IMT™ is given in a regimen including low-dose pre-dose cyclophosphamide (to reduce suppression of the immune response) and post-dose interferon-alpha (to boost the immune response).  The second clinical trial, BRI-ROL-001 (listed in ClinicalTrials.gov as NCT03328026), is a rollover study of Bria-IMT™ in combination with Keytruda® [pembrolizumab] or Yervoy® [ipilimumab].

Patient recruitment is on schedule despite interruption due to temporary shutdown of some clinical sites, affected by wildfires and hurricanes. Seven patients have enrolled in the WRI-GEV-007 clinical trial with 6 treated to date (1 patient dropped out after cyclophosphamide pre-treatment and did not receive Bria-IMT™). Based on results to-date, Bria-IMT™ has been very well tolerated and the majority of adverse events were limited to expected minor local irritation at the injection sites.  No serious adverse events related to Bria-IMT™ have been reported and no new or unexpected safety issues related to Bria-IMT™ have been observed.  The Phase I portion of the study has been successfully completed, and the Phase IIa portion is currently enrolling.

One patient is worth discussing in detail. This 73-year-old woman had breast cancer diagnosed in 1995.  She developed liver metastases in 2010, and then lung metastases in 2017. Prior treatments included surgery, radiation therapy, hormonal therapy and seven rounds of chemotherapy with 8 different chemotherapy agents. She received 5 cycles of Bria-IMT™ over the first 3 months of treatment, then 3 additional cycles over the following 3 months (6 months total).  Evaluation was performed after 3 months and 6 months. After 3 months, despite the extensive prior therapy, her scans noted that, “there has been a clear response in the multiple bilateral pulmonary nodules” indicating that several lung tumors had disappeared or decreased in size.  This response was maintained after 6 months of treatment with Bria-IMT™.  The liver tumors were stable to slightly increased at 3 months, and then progressed after 6 months.

Like the patient reported previously by Dr. Wiseman, BriaCell’s Scientific Founder, in a proof-of-concept clinical study, this patient is a double match with Bria-IMT™ at two specific biomarkers (HLA-A and HLA-DRB3).  This is highly significant, as it supports our BriaDX™ hypothesis that these biomarkers can be used to select the patients most likely to respond to Bria-IMT™ therapy.  We also noted in this patient that, while circulating tumor-associated cells decreased following the initial treatment, the expression of PD-L1, a molecule that suppresses the immune response, increased during treatment. This suggests that treating this patient (and other similar patients) with Bria-IMT™ in combination with a potent PD-1 inhibitor such as Keytruda® [pembrolizumab] may be a highly effective method to improve the efficacy of the treatment and patient outcomes.

A third clinical site was recently added to the study and several patients are being evaluated for the WRI-GEV-007 study. Discussions are ongoing with two additional clinical sites which are expected to be added in the near future. The combination rollover study, BRI-ROL-001, is available to enroll patients.

Other activities remain on track.  The companion diagnostic, BriaDX™, has been bolstered by the important supporting data for the HLA biomarker matching hypothesis noted above.  BriaCell is also developing an off-the-shelf, personalized immunotherapy (Bria-OTS™) to treat a much wider patient population (with ~90% of the population being a double-match with Bria-OTS™).  In collaboration with University of Zurich, Switzerland, BriaCell is testing other drugs/product candidates that are expected to boost the effectiveness of Bria-IMT™ and Bria-OTS™.

Ongoing work in the small molecule program to select protein kinase C delta inhibitors for cancer and fibrotic diseases is also progressing according to our timelines. The medicinal chemistry work is being performed at Colorado State University where the current library of compounds available is being augmented.

BriaCell is an immuno-oncology focused biotechnology company developing a targeted and safe approach to the management of cancer. Immunotherapy has come to the forefront of the fight against cancer, harnessing the body’s own immune system in recognizing and selectively destroying cancer cells while sparing normal ones. Immunotherapy, in addition to generally being more targeted and less toxic than commonly used types of chemotherapy, is also thought to be a potent approach with the potential to prevent cancer recurrence.

Bria-IMT™ (SV-BR-1-GM), the Company’s lead product candidate, is derived from a breast cancer cell line genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system by allowing the body to recognize and eliminate cancerous cells by inducing tumor-directed T cell and potentially antibody responses.

The results of two previous proof-of-concept clinical trials (one with the precursor cell line not genetically engineered to produce GM-CSF and one with Bria-IMT™) produced encouraging results in patients with advanced breast cancer. Most notably, one patient with metastatic breast cancer responded to Bria-IMT™ with substantial reduction in tumor burden including breast, lung, soft tissue and brain metastases. The company is currently conducting a Phase I/IIa clinical trial for Bria-IMT™ in patients with advanced breast cancer.  This trial is listed in ClinicalTrials.gov as NCT03066947.  The trial is being conducted along with the co-development of BriaDX™, the Company’s companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018. Additionally, the FDA recently approved the roll-over combination study of Bria-IMT™ with pembrolizumab [Keytruda; manufactured by Merck & Co., Inc.] or ipilimumab [Yervoy; manufactured by Bristol-Myers Squibb Company] for patients previously treated with Bria-IMT™ in the Company’s ongoing Phase I/IIa clinical trial in advanced breast cancer. The roll-over trial is listed in ClinicalTrials.gov as NCT03328026.

BriaCell is also developing Bria-OTS™, an off-the-shelf personalized Immunotherapy.  Bria-OTS™ consists of 14 individually pre-manufactured genetic alleles. BriaCell’s BriaDX™ companion diagnostic reveals a patient’s specific HLA-types and the 2 best matching alleles are administered to the patient. BriaCell’s 14 alleles (8 Class I and 6 Class II) cover approximately 90% of the Breast Cancer population while eliminating the complex manufacturing logistics required for other personalized immunotherapies. Bria-OTS™ is a personalized therapy without the need for personalized manufacturing.

BriaCell is also developing novel, selective protein kinase C delta (PKCδ) inhibitors. PKCδ inhibitors have shown activity in a number of pre-clinical models of RAS genes’ transformed cancers including breast, pancreatic, non-small cell lung cancer and neuroendocrine tumors (such as carcinoid tumors).

For additional information on BriaCell, please visit our website: http://briacell.com.

Researchers Detect a Loophole in Chronic Lymphocytic Leukemia Treatment

A team of researchers in Italy and Austria has determined that a drug approved to treat chronic lymphocytic leukemia (CLL) may be less effective in a particular subset of patients. The study, which will be published January 4 in the Journal of Experimental Medicine, reveals that ibrutinib has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d, but combining ibrutinib treatment with drugs that block CD49d activation could prevent the tumor cells from sheltering in lymphoid organs.

CLL is the most common leukemia in adults, and it is characterized by the presence of cancerous B cells that accumulate in the lymph nodes, spleen, and liver. Ibrutinib reallocates CLL cells from lymph nodes into the blood by inhibiting Bruton’s tyrosine kinase (BTK), a key enzyme in the B cell receptor (BCR) signaling pathway.

BCR signaling promotes the survival and differentiation of normal, healthy B cells in several ways, including by activating the adhesion receptor VLA-4, which attaches B cells to other, supportive cells within lymph nodes. One of the subunits of VLA-4, CD49d, is highly expressed in about 40% of CLL patients. These patients tend to have poorer outcomes than patients that do not express CD49d, but the role of VLA-4 in CLL is unclear.

A team of researchers led by Antonella Zucchetto and Valter Gattei of the CRO Aviano National Cancer Institute in Italy and Tanja Nicole Hartmann of the Paracelsus Medical University in Salzburg, Austria, found that BCR signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness. Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully hinder the pathway from activating VLA-4 and enhancing cell adhesion.

The researchers analyzed three different cohorts of CLL patients from Italy and the United States. In all three groups, patients expressing higher levels of CD49d showed reduced responses to ibrutinib treatment: the drug appeared to be less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.

“Our results suggest that VLA-4–expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” says Zucchetto. “This activation leads to enhanced retention of VLA-4–positive CLL cells in tissue sites, thereby affecting patient outcome.”

In addition to the ibrutinib target BTK, BCR signaling can proceed through an alternative enzyme called phosphatidylinositide 3-kinase. The researchers found that simultaneously inhibiting both BTK and phosphatidylinositide 3-kinase completely blocked VLA-4 activation in CLL cells.

“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4–mediated retention of leukemic cells in protective tissue compartments,” says Gattei.

Immune Cells Play Key Role in Early Breast Cancer Metastasis Even Before a Tumor Develops

Mount Sinai researchers have discovered that normal immune cells called macrophages, which reside in healthy breast tissue surrounding milk ducts, play a major role in helping early breast cancer cells leave the breast for other parts of the body, potentially creating metastasis before a tumor has even developed, according to a study published in Nature Communications.

The macrophages play a role in mammary gland development by regulating how milk ducts branch out through breast tissue. Many studies have also proven the importance of macrophages in metastasis, but until now, only in models of advanced large tumors. By studying human samples, mouse tissues, and breast organoids, which are miniaturized and simplified versions of breast tissue produced in the lab, the new research found that in very early cancer lesions, macrophages are attracted to enter the breast ducts where they trigger a chain reaction that brings early cancer cells out of the breast, said lead researcher Julio Aguirre-Ghiso, PhD, Professor of Oncological Sciences, Otolaryngology, Medicine, Hematology and Medical Oncology at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.

This research shows that macrophages’ relationship with normal breast cells is co-opted by early cancer cells that activate the cancer-causing HER2 gene, helping in this newly-discovered role of these immune cells. The findings from this study could eventually help pinpoint biomarkers to identify cancer patients who may be at risk of carrying potential metastatic cells due to these macrophages and potentially lead to the development of novel therapies that prevent early cancer metastasis.

Early treatment of high-risk patients may prevent the formation of deadly metastasis better than the current standard of treating metastatic disease only once it has occurred, said key researcher Miriam Merad, MD, PhD, Director of the Precision Immunology Institute and the Human Immune Monitoring Center and co-leader of the Cancer Immunology program at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.

“Our study challenges the dogma that early diagnosis and treatment means sure cure,” Dr. Aguirre-Ghiso said. “In this study and in our previous studies, we present mechanisms governing early dissemination.  This work further sheds light onto the mysterious process of early dissemination and cancer of an unknown primary tumor.”

Researchers hope to build on this study by identifying which macrophages specifically control early dissemination. They also hope to further detail how early disseminated cancer cells interact with macrophages in the lungs where metastases eventually form and how this interaction can be targeted to prevent metastasis.

“Here, we have identified how macrophages and early cancer cells form a ‘microenvironment of early dissemination’ and show that by disrupting this interaction we can prevent early dissemination and ultimately deadly metastasis,” said Dr. Merad. “This sheds light onto the mysterious process of early dissemination and for patients who have metastasis cancer that came from an unknown source.”

How Defeating THOR Could Bring a Hammer Down on Cancer

It turns out Thor, the Norse god of thunder and the Marvel superhero, has special powers when it comes to cancer too.

Researchers at the University of Michigan Comprehensive Cancer Center uncovered a novel gene they named THOR while investigating previously unexplored regions of the human genome – the dark matter of the human genome.

They characterized a long non-coding RNA (lncRNA) that is expressed in humans, mice and zebrafish. It’s unusual for this type of RNA to be conserved throughout species like this. The team’s thinking was that if the RNA plays a role in other animals and species besides humans, it must be important.

“Genes that are evolutionarily conserved are likely important for biological processes. The fact that we found THOR to be a highly conserved lncRNA was exciting. We chose to focus on it with the thought that it has been selected by evolution for having important functions,” says Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine.

In fact, the researchers found this particular lncRNA plays a role in cancer development. And that knocking it out can halt the growth of tumors.

This is the first group to identify and characterize THOR, which stands for Testis-associated Highly-conserved Oncogenic long non-coding RNA. They published their results in Cell.

It’s an early example of how this previously unexplored portion of the genome could lead to a potential new way of attacking cancer.

In 2015, Chinnaiyan’s team published a paper analyzing the global landscape of lncRNAs, which had been considered dark matter because so little was known about it. They identified thousands of potential lncRNAs that might warrant future study.

THOR rose to the top of the list because it was evolutionarily highly conserved. It was also highly expressed, specifically in testes cells. It had little to no expression in other types of adult normal tissue.

Because THOR is highly conserved, researchers were able to study it in mice and zebrafish, as well as in human cells.

“That is one of the challenges of studying lncRNAs that are not conserved. If they’re not conserved in model systems, they are difficult to characterize. Here, because THOR is so highly conserved, we were able to look at its expression and function in zebrafish models,” Chinnaiyan says.

In addition to finding THOR expression in normal testis tissue, the researchers found it was highly expressed in some subsets of cancers, particularly lung cancer and melanoma. As they investigated THOR, they found its expression had a direct impact on cancer development. If they knocked down THOR in cell lines expressing it, tumor growth slowed. If they overexpressed THOR, cells grew faster. And when they eliminated THOR from normal cells, the cells continued to develop normally, suggesting it only impacts cancer cells.

“We’ve gone through a lot of lncRNAs to get to that. Most of the ones we test don’t have a clear function like this,” Chinnaiyan says.

Researchers also found that THOR impacted proteins called IGFBPs, which are thought to be involved in stabilizing RNAs. Knocking down THOR inhibited IGFBP activity.

“If we perturb THOR function, we disturb the ability to stabilize RNA. This inhibits cell proliferation,” Chinnaiyan says. Conversely, when researchers overexpressed THOR, cells grew faster.

Chinnaiyan suggests THOR could be a good target for drug development because blocking it does not impact normal cells. That would likely mean fewer toxic side effects. In future studies, the researchers will look at how to create a compound that binds with THOR in a complimentary sequence designed to knock it down. This approach, known as antisense oligonucleotides, has been used successfully in other contexts.

UK Study Finds Biomarker Targets to Make Drugs More Effective in Fighting Cancer

A new study published in Nature Communications and led by University of Kentucky Markey Cancer Center researcher Qing-Bai She identifies biomarker targets that may make existing drugs more effective in fighting certain cancers.

The mTOR protein is a central regulator of cell growth and division. Abnormal activation of mTOR protein results in limitless cell division in many human cancers. Though mTOR-targeted drugs exist, their effectiveness has so far been limited, possibly due to the loss of the mTOR downstream effector 4E-BP1, a key repressor of protein production.

The study identifies Snail, a nuclear transcription regulator known to promote cancer progression, as a strong repressor of 4E-BP1 expression. She’s team found an inverse correlation between Snail and 4E-BP1 levels in colorectal cancer, the second leading cause of cancer-related mortality in the United States. This study shows promise that the Snail level may serve as a predictive marker to tailor personalized treatments using mTOR-targeted drugs. Physicians may be able to prescribe treatment for cancers that have high Snail/low 4E-BP1 activities, using cancer drugs that are already in clinical development.

“This finding has significant clinical ramification, because incorporating the analysis of Snail and 4E-BP1 expression in cancers may help to prospectively identify resistance to mTOR-targeted drugs in the clinic,” said She, associate professor in the UK Department of Pharmacology & Nutritional Sciences.

Combination Strategy Could Hold Promise for Ovarian Cancer

 Johns Hopkins Kimmel Cancer Center researchers demonstrated that mice with ovarian cancer that received drugs to reactivate dormant genes along with other drugs that activate the immune system had a greater reduction of tumor burden and significantly longer survival than those that received any of the drugs alone.

The study already spurred a clinical trial in ovarian cancer patients. The investigators, led by graduate student Meredith Stone, Ph.D.; postdoctoral fellow Kate Chiappinelli, Ph.D.; and senior author Cynthia Zahnow, Ph.D., believe it could lead to a new way to attack ovarian cancer by strengthening the body’s natural immune response against these tumors. It was published in the Dec. 4, 2017, issue of the Proceedings of the National Academy of Sciences.

Ovarian cancer is currently the leading cause of death from gynecological malignancies in the U.S. “We’ve taken two types of therapies that aren’t very effective in ovarian cancer and put them together to make them better at revving up the immune system and attacking the tumor,” says Zahnow, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Zahnow says that a class of immunotherapy drugs known as checkpoint inhibitors, currently being studied at the Bloomberg~Kimmel Institute for Cancer Immunotherapy, helps the immune system recognize cancers and fight them off. The drugs have shown success in treating melanoma, nonsmall cell lung cancer and renal cell cancers, but they have had only modest effects on ovarian cancer.

Similarly, another class of drugs known as epigenetic therapies has been used to treat some types of cancer by turning on genes that have been silenced— either by the presence of chemical tags, known as methyl groups, or by being wound too tightly around protein spools, known as histones—but these drugs haven’t been effective against ovarian cancer either.

Zahnow and her colleagues became inspired to investigate a new way to treat ovarian cancer by two recent publications from their group that showed epigenetic drugs turn on immune signaling in ovarian, breast and colon cancer cells (Li et al., Oncotarget 2014). These immune genes are activated when epigenetic therapy turns on segments of ancient retroviruses that activate type 1 interferon signaling in the cells (Chiappinelli et al., Cell 2015).  Stone, Chiappinelli and Zahnow wanted to know if this increase in immune signaling could lead to the recruitment of tumor killing immune cells to the cancer.

Zahnow and her colleagues worked with a mouse model of the disease in which mouse ovarian cancer cells are injected into the animals’ abdomens to mimic human disease. These cells eventually develop into hundreds of small tumors, which cause fluid to collect within the abdomen, a condition known as ascites. Floating in this fluid is a milieu of both cancer and immune cells, offering a convenient way to keep tabs on both the tumor and the animals’ immune response.

The researchers started by pretreating the ovarian cancer cells outside of the animal in a culture dish with a DNA methyltransferase inhibitor (a drug that knocks methyl groups from DNA) called 5-azacytidine (AZA). After injecting these cells into mice, the researchers found that animals receiving the pretreated cells had significantly decreased ascites or tumor burden and significantly more cancer-fighting immune cells in the ascites fluid compared to those injected with untreated cells. These cells also had increased activity in a variety of genes related to immune response. Pretreating these cells with histone deacetylase inhibitors (HDACis), which help DNA uncoil from histones, didn’t affect the animals’ ascites or boost their immune response.

These early findings suggested that changes in gene activity induced by AZA cause the tumor cells themselves to summon immune cells to their location. In addition, when the researchers transplanted untreated cells into mice and treated the animals with both AZA and an HDACi, significantly more immune cells were in the ascites fluid, suggesting that the HDACi was acting on the animals’ immune systems. These mice also had decreased ascites, lower tumor burden and longer survival than mice that received just AZA.

When the researchers treated the mice with both AZA and an HDACi, along with an immune checkpoint inhibitor, they got the greatest response—the highest decreases in ascites and tumor burden, and the longest survival. Further experiments using immunocompromised mice showed that the immune system is pivotal to the action of these drugs, rather than the drugs themselves acting directly to kill tumor cells.

“We think that AZA and the HDACis are bringing the soldiers, or immune cells, to the battle. But the checkpoint inhibitor is giving them the weapons to fight,” says Zahnow, who also collaborated with epigenetics scientist Stephen Baylin, M.D., on this project.

The preclinical data generated through this study is already being used to help patients with ovarian cancer through an ongoing clinical trial to test the effectiveness of combining AZA and a checkpoint inhibitor. Future trials may add an HDACi to determine if it affects outcomes.

“Combining epigenetic therapy and a checkpoint blocker leads to the greatest reduction in tumor burden and increase in survival in our mouse model and may hold the greatest promise for our patients,” says Zahnow.

Promising new treatment for rare pregnancy cancer leads to remission in patients

Three out of four patients with the cancerous forms of gestational trophoblastic disease (GTD) went into remission after receiving the immunotherapy drug pembrolizumab in a clinical trial carried out by researchers at Imperial College London.

The trial, which took place at Charing Cross Hospital, part of Imperial College Healthcare NHS Trust, is the first to show that pembrolizumab can be used to successfully treat women with GTD.

The team hopes that this small early stage study, published in The Lancet, could provide another treatment option for women who have drug-resistant GTD and lead to a 100 per cent cure rate.

Professor Michael Seckl, lead author of the study, said:

“We have been able to show for the first time that immunotherapy may be used to cure patients of cancerous GTD. The current treatments to tackle GTD cure most cases of the disease. However, there are a small number of women whose cancers are resistant to conventional therapies and as a result have a fatal outcome. Immunotherapy may be a life-saving treatment and can be used as an alternative to the much more toxic high dose chemotherapy that is currently used. These are landmark findings that have implications on how we treat the disease in the UK and around the world.”

GTD is the term used to describe abnormal cells or tumors that start in the womb from cells that normally give rise to the placenta. They are extremely rare but can happen during or after pregnancy.

The most common type of GTD is so-called molar pregnancy where a foetus doesn’t form properly in the womb and a baby doesn’t develop, instead a lot of abnormal placental-like tissue forms. A molar pregnancy can usually be treated with a simple procedure to remove the growth of abnormal placental cells from the womb but some of this material is usually left behind. This can become cancerous and spread to other parts of the body, requiring lifesaving chemotherapy. In around one in 50,000 pregnancies cancerous GTD known as choriocarcinoma develops after other types of pregnancy including normal pregnancies and this also requires life-saving chemotherapy.

Globally, 18,000 women are diagnosed annually with cancerous forms of GTD, most of whom are cured with chemotherapy or surgery. However, up to five per cent of these women’s outcomes are fatal due to factors such as chemotherapy resistance and rare forms of the cancer such as placental site trophoblastic tumours (PSTT) that develop four or more years after the causative pregnancy has ended.

Immunotherapy is a type of treatment that helps a person’s immune system fight diseases such as a cancer. The immune system fights off invading infections but can miss cancer cells. Pembrolizumab works by stimulating the body’s immune system to target and kill cancer cells. The drug is also used to treat some cases of lung cancer and melanoma.

The researchers wanted to test whether pembrolizumab could be used to treat four patients aged between 37-47 years with multi-drug resistant cancerous GTD.

The patients were given pembrolizumab intravenously every three weeks over a period of about six months between 2015-2017.

The trial also took place at the Department of Women’s and Children’s Health in Stockholm.

The researchers then carried out a blood test to measure the amount of the pregnancy hormone hCG in their system, which is an indicator of whether abnormal placental cells are left in the womb or elsewhere in the body.

They found that most patients’ hCG levels started to fall by three doses and once their hCG was normal five consolidation doses of pembrolizumab were given before stopping treatment. This contrasts with melanoma and lung cancer where this drug is given to patients continuously for two or more years. The patients remain without signs of cancer recurrence for between five months to over two years on follow-up.

The researchers also found that pembrolizumab was well tolerated in GTD patients. This is in comparison to chemotherapy which can cause nausea, vomiting and hair loss.

The team suggests that this could have cost saving implications for the NHS as six months of the drug costs about £30,000 per patient compared to two rounds of high dose chemotherapy which costs £70,000.

Melody Ransome took part in the clinical trial after being diagnosed with choriocarcinoma, which had spread from her uterus to her liver, kidney, pancreas, lungs and brain. Melody was given the immunotherapy drug over five months in 2015. After her second infusion, Melody’s hCG levels dropped by 50 per cent and she was in remission two months later. Melody continues to be in remission two and half years after receiving the immunotherapy.

“Before the trial I was being treated by high dosage of chemotherapy which made me feel awful. I experienced hair loss, fatigue and it was difficult to carry out normal tasks like looking after my two children. On top of that, the chemotherapy wasn’t working.

This all changed for me once I was given the immunotherapy drug. Each week I felt better and better. I had no side effects and I started to feel more normal. When I was told that I was in remission I was shocked that the treatment had worked in such a short amount of time. It’s been life changing and I’ve been able to enjoy spending quality time with my family again. I used to be able to swim 40 lengths before my illness and since having the immunotherapy I am close to it. It’s been an incredible journey.”

Following the findings, NHS England has agreed provisional funding to treat some cases of GTD with pembrolizumab for two years at Charing Cross and Sheffield Hospitals where these cases are managed in the UK.

The researchers will carry out a further study to assess the effects of pembrolizumab on fertility to see whether it can be offered to women at an earlier stage of treatment.

FDA Approves the Roll-Over Combination Study with Checkpoint Inhibitor Immunotherapies to Allow Continued Access to BriaVax™ in Patients with Advanced Breast Cancer

The FDA has approved the roll-over combination study of the investigational breast cancer vaccine, BriaVax™ with pembrolizumab {Keytruda; manufactured by Merck & Co., Inc. or ipilimumab {Yervoy; manufactured by Bristol-Myers Squibb Company for patients previously treated with BriaVax™ from the ongoing Phase I/IIa Clinical Trial in Advanced Breast Cancer.

BriaVax™ is a whole-cell breast cancer vaccine genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system by allowing the body to recognize and eliminate cancerous cells by inducing tumor-directed T cell and potentially antibody responses.

This roll-over combination study allows the patients who did not respond to BriaVax™ (monotherapy) treatment to be treated and continue to receive the potential clinical benefits of the vaccine in combination with either pembrolizumab or ipilimumab. This approach is based on the hypothesis that both pembrolizumab and ipilimumab may improve the anti-tumor activity of vaccine in patients with advanced breast cancer. Safety and efficacy data will be evaluated.

“We are very excited to evaluate the effects of BriaVax™ with other approved anti-tumor immunotherapeutic agents. We expect this study to extend and potentiate the clinical benefits of BriaVax™ in advanced breast cancer patients,” stated Dr. Williams, BriaCell’s President & CEO in a press release. “We look forward to expanding our clinical study and exploring potential immunotherapy partnerships with leading pharmaceutical companies in the future, and we are pleased with the FDA decision,” Dr. Williams added.

The clinical investigators will work closely with Cancer Insight, LLC, BriaCell’s contract research organization, to manage the clinical and regulatory aspects of the clinical trial for the roll-over combination study of BriaVax™ on behalf of BriaCell. More information on the roll-over combination study of BriaVax™ with either ipilimumab or pembrolizumab will be available on ClinicalTrials.gov (Study identifier: BRI-ROL-001).

Manufactured by Merck & Co., Inc., KEYTRUDA® (pembrolizumab) is a prescription medicine that may treat certain cancers by working with the immune system. It has been approved for the treatment of a number of cancer indications excluding breast cancer.

Manufactured by Bristol-Myers Squibb Company, YERVOY® (ipilimumab) is a prescription medicine used in adults and children 12 years and older to treat melanoma (a kind of skin cancer) that has spread (metastatic) or cannot be removed by surgery (unresectable). It is a monoclonal antibody that works to activate the immune system and enabling them to recognize and destroy cancer cells.

BriaVax™ is a whole-cell breast cancer vaccine genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system. Previously, a small Phase I study documented very prompt and near complete regression of metastatic breast cancer deposits in the breast, lung, soft tissue, and even the brain.

The ongoing open-label Phase I/IIa study will evaluate BriaVax™ in up to 40 advanced breast cancer patients. This trial is listed in ClinicalTrials.gov as NCT03066947. The trial is being conducted along with the co-development of BriaDx™, our companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018.

BriaCell is an immuno-oncology focused biotechnology company developing a targeted and safe approach to the management of cancer. BriaCell’s mission is to serve late-stage cancer patients with no available treatment options.

Immunotherapy has come to the forefront of the fight against cancer, harnessing the body’s own immune system in recognizing and selectively destroying the cancer cells while sparing normal ones. Immunotherapy, in addition to generally being more targeted and less toxic than commonly used types of chemotherapy, is also thought to be a strong type of approach aimed at preventing cancer recurrence.

The results of two previous Phase I clinical trials (one with the precursor cell line not genetically engineered to produce GM-CSF and one with BriaVax™) have been encouraging in patients with advanced breast cancer. Most notably, one patient with metastatic breast cancer responded to BriaVax™ with substantial reduction in tumor burden including lung and brain metastases. The company is currently conducting a Phase I/IIa clinical trial for BriaVax™ in patients with advanced breast cancer whose disease has progressed following at least one prior treatment course.

This trial is listed in ClinicalTrials.gov as NCT03066947.  The trial is being conducted along with the co-development of BriaDx™, our companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018.

In a previous Phase I setting, a patient with metastatic breast cancer responded to BriaVax™ with objective reduction in tumor burden. To expand on this finding, after updating the clinical protocol of the original investigational new drug (IND) application, an open-label Phase I/IIa clinical trial enrolling up to 40 late stage breast cancer patients with recurrent and/or metastatic disease has been launched. Patients will be administered BriaVax™ every two weeks for the first month of treatment, then monthly up to one year.

The primary objective of the Phase I/IIa clinical trial is to evaluate the safety of BriaVax™ in study subjects, and the principal secondary objective is an evaluation of the tumor size reduction. Tumor response will be monitored every three months during the study. The trial will also evaluate progression-free survival (PFS) and overall survival (OS).

For additional details regarding the clinical trial, please visit:
https://www.clinicaltrials.gov/ct2/show/NCT03066947

Public-Private Consortium Aims to Cut Preclinical Cancer Drug Discovery from Six Years to Just One

Scientists from two U.S. national laboratories, industry and academia today launched an unprecedented effort to transform the way cancer drugs are discovered by creating an open and sharable platform that integrates high-performance computing, shared biological data from public and industry sources and emerging biotechnologies to dramatically accelerate the discovery of effective cancer therapies.

The goal of the consortium – Accelerating Therapeutics for Opportunities in Medicine (ATOM) – is to create a new paradigm of drug discovery that would reduce the time from an identified drug target to clinical candidate from the current approximately six years to just 12 months. ATOM aims to transform cancer drug discovery from a time-consuming, sequential and high-risk process into an approach that is rapid, integrated and with better patient outcomes — using supercomputers to pretest many molecules simultaneously for safety and efficacy.

The consortium comprises the Department of Energy’s Lawrence Livermore National Laboratory (LLNL), GSK, the National Cancer Institute’s Frederick National Laboratory for Cancer Research (FNLCR), and the University of California, San Francisco (UCSF). ATOM welcomes additional public and private partners who share the vision.

“The goals of ATOM are tightly aligned with those of the 21st Century Cures Act, which aims in part to enable a greater number of therapies to reach more patients more quickly,” said FNLCR Laboratory Director David Heimbrook. “Although initially focused on precision oncology – treatments targeted specifically to the characteristics of the individual patient’s cancer – the consortium’s discoveries could accelerate drug discovery against many diseases.”

ATOM will develop, test and validate a multidisciplinary approach to drug discovery in which modern science, technology and engineering, supercomputing simulations, data science and artificial intelligence are highly integrated into a single drug-discovery platform that can untimately be shared with the drug development community at large.

“As we have learned more about what modern supercomputers can do, we’ve gained confidence that this approach can make a big difference in creating medicines,” said John Baldoni, senior vice president, R&D at GSK. “We must do all that we can to reduce the time it takes to get medicines to patients. GSK is working to set a precedent with pharmaceutical companies by sharing data on failed compounds.”

GSK will initially contribute chemical and in vitro biological data for more than 2 million compounds from its historic and current screening collection, as well as preclinical and clinical information on 500 molecules that have failed in development but could help accelerate development of new compounds by providing knowledge about the underlying biology of candidate compounds and that of the human body. Combined with data on successful drugs, GSK’s offering represents a broad base of information for ATOM researchers. In addition, GSK will provide expertise in drug discovery and development, computational chemistry and biology.

The ATOM team will combine data provided by GSK with publicly available data, and that of future consortium members, to generate new dynamic models that can better predict how molecules will behave in the body compared to the current iterative and time-consuming practices. In this effort, LLNL will contribute its best-in-class supercomputers, including its next-generation system Sierra, as well as its expertise and innovative approaches to modeling and simulation, cognitive computing, machine learning and algorithm development. More broadly, by tackling the ambitious challenge of cancer therapies, ATOM will drive technologies vital to the core missions of the Department of Energy and National Nuclear Security Administration (NNSA).

“ATOM is a novel public-private partnership that draws on the lab’s unique capabilities to create a paradigm change in drug development,” said LLNL Director Bill Goldstein. “It will help to strengthen U.S. leadership in high-performance computing and, by speeding the discovery of therapeutics, contribute to biosecurity.”

For its part, FNLCR will contribute from its wealth of scientific expertise in precision oncology, computational chemistry and cancer biology, as well as support for open sharing of data sets and predictive modeling and simulation tools. UCSF will provide expertise from a long history of innovation in drug discovery and medicine to improve the lives of patients.

“We at UCSF are eager to lend our expertise to this effort,” said UCSF Chancellor Sam Hawgood, MBBS. “UCSF scientists and clinicians have long been leaders in drug discovery, therapeutics, and cancer biology with the UCSF Helen Diller Family Comprehensive Care Center among the top-ranked cancer institutes in the country. Our role with ATOM is therefore in lock step with UCSF’s mission of advancing health worldwide.”

ATOM welcomes additional public and private partners who share the vision of the consortium, which will have physical headquarters in the Mission Bay neighborhood of San Francisco, adjacent to UCSF’s newest campus.

Researchers quantify breast cancer risk based on rare variants and background risk

Rare variants combined with background genetic risk factors may account for many unexplained cases of familial breast cancer, and knowing the specific genes involved could inform choice of prevention and treatment strategies, according to findings presented in a plenary session at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Fla.

Researchers Na Li, MD, who presented the work; Ian Campbell, PhD, lead investigator; and their colleagues at the Peter MacCallum Cancer Centre in Melbourne, Australia, focused their study on patients at high risk of breast cancer: those with a personal or family history who were seeking an explanation.

“When you know which gene is conferring the risk of breast cancer, you can provide a more precise estimate of risk, know what to expect and watch out for, and tailor risk management strategies to the patient,” said Dr. Campbell. Unfortunately, in about half of these high-risk patients, no known genetic cause was found, suggesting a more complicated explanation. In such cases, cancer geneticists had long suspected that polygenic risk (risk conferred by a combination of genetic variants) was involved.

Genes do not work on their own, but rather as part of one’s overall genetic context, explained Dr. Li. “That ‘polygenic risk’ background is like a landscape full of hills and valleys, with each risky variant like a house on top of it,” she said. “If you inherit a high-risk variant – a tall house – but live in a valley, your overall risk of breast cancer may end up being average because your genetic landscape pulls it down.”

The concept of background genetic risk is not new, but for many years, scientists did not have the tools to collect and analyze the thousands of genomes needed to quantify it. Recent improvements in next-generation sequencing technology have addressed this challenge. As a result, Dr. Li and colleagues were able to sequence up to 1,400 candidate breast cancer genes in 6,000 familial breast cancer patients and 6,000 cancer-free controls. In this large sample, they searched for potential cancer-associated genes suggested by the literature, collaborators, and their own previous results, and identified at least 46 genes that were at least twice as likely to have mutations among participants with breast cancer than in those without.

They also used the data to calculate a polygenic risk score for each patient, and combined this score with data on their high and moderate-risk variants to estimate each patient’s overall risk of developing breast cancer. In the coming years, the researchers plan to expand the study internationally to further test and refine their findings across populations. They also hope to bring these more precise risk estimates into the clinic, to more accurately reassure women about their personal risk of cancer, or – if risk is high – advise preventive strategies such as screening at a younger age.

According to William V. Williams, MD, FRCP, CEO of BriaCell Therapeutics Corp. news on new variants are essential and extremely useful in tailoring and customizing their BriaVax™ breast vaccine technology with those variants in order to teach the body to recognize and eliminate cancerous cells. Their whole-cell breast cancer vaccine is genetically engineered to release granulocyte macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system. “Breast cancer is an evolving field, there are different sub types of breast cancer. As we know more about the genetics of breast cancer this will allow us to develop novel therapies to treat those different variants, that is part of what we are doing with our vaccines,” he told Modern Wall Street.

Blood Test for HPV May Help Predict Risk in Cancer Patients

A blood test for the human papillomavirus, or HPV, may help researchers forecast whether patients with throat cancer linked to the sexually transmitted virus will respond to treatment, according to preliminary findings from the University of North Carolina Lineberger Comprehensive Cancer Center.

HPV can cause oropharyngeal cancer, which is a cancer of the throat behind the mouth, including the base of the tongue and tonsils. Studies have shown that patients with HPV-positive oropharyngeal cancer have better outcomes than patients whose cancer is not linked to the virus.

Preliminary findings presented at this year’s American Society for Radiation Oncology Annual Meeting suggest a genetic test for HPV16 in the blood could be useful to help assess risk for patients, and could help identify patients suitable for lower treatment doses.

“Our work on this blood test is ongoing, but we are optimistic that ‘liquid biopsy’ tests such as ours may be useful in the personalization of therapy for many patients with HPV-associated oropharyngeal cancer,” said the study’s senior author Gaorav P. Gupta, MD, PhD, UNC Lineberger member and assistant professor in the UNC School of Medicine Department of Radiation Oncology.

To avoid over-treating patients and to spare them from toxic treatment side effects, UNC Lineberger’s Bhisham Chera, MD, an associate professor in the radiation oncology department, led studies testing whether favorable-risk patients with HPV-positive oropharyngeal cancer can be treated successfully with lower doses of radiation and chemotherapy. A phase II clinical trial using this de-intensified regimen have shown “excellent” cancer control, Chera said.

The researchers used a number of selection criteria to identify patients who can benefit from lower-doses: patients had to be positive for HPV, and they had to have smoked fewer than 10 pack years. Chera said this system is not perfect, however. The researchers have seen cancer recur in non-smoking patients as well as “excellent” cancer control in longtime smokers.

“This has led us to question whether we can get better prognostication with other biomarkers,” Chera said.

They developed a test that can detect HPV16 circulating in the blood, and found that circulating HPV16 DNA was detectable using the test in the majority of a group of 47 favorable-risk oropharyngeal cancer patients.

In a finding that seems counterintuitive, they discovered that very low or undetectable HPV16 pretreatment levels in their blood actually had higher risk of persistent or recurrent disease for chemotherapy and radiation treatment. In contrast, patients with high pretreatment levels of HPV16 in their blood had 100 percent disease control.

They hypothesized that, potentially, the patients with undetectable/low pre-treatment HPV16 levels in the blood may have different, more radiation/chemotherapy resistant cancers.

“Our current theory is that these patients with low or undetectable levels of HPV16 have a different genetic makeup—one that is perhaps less driven purely by HPV, and thus potentially less sensitive to chemotherapy and radiation,” Gupta said. “We are performing next generation sequencing on these patients to search for additional genetic markers that may give us a clue regarding why they have a worse prognosis.”

They also identified a subset of patients who rapidly cleared the HPV16 from their blood. Researchers hypothesize that they could use their findings to further stratify patients who may be eligible for lower intensity treatment.

“A tantalizing – and yet currently untested – hypothesis is whether this subset of ultra-low risk patients may be treated with even lower doses of chemoradiotherapy,” Gupta said.

Genetic Targets to Chemo-Resistant Breast Cancer Identified

Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer.

Increased activity of two genes, MCL1 and MYC, is associated with the development of chemotherapy resistance. The increased action of these two genes boosts mitochondrial oxidative phosphorylation, which promotes the growth of chemotherapy-resistant cancer stem cells, the research showed.

“Alterations in these two genes are easily detectable with tumor gene tests in current use. Combinations of drugs that inhibit MCL1 or MYC, or both, have the potential to reduce the development of chemotherapy resistance and should be studied in clinical trials,” said Dr. Arteaga, Professor of Internal Medicine at UT Southwestern Medical Center. Dr. Arteaga holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology.

Most breast cancers can be treated with hormone therapy, but about 15 percent of cases are triple negative breast cancer, meaning the cancer cells are not influenced by hormones like estrogen or progesterone. These triple negative breast cancers must, therefore, be treated with chemotherapy, which is toxic to healthy cells as well as cancer cells. Furthermore, most triple negative breast cancers eventually become resistant to chemotherapy and the cancer then spreads unchecked.

Drugs that inhibit activity of the MCL1 or MYC genes are in development, Dr. Arteaga said. These drugs, given in conjunction with standard chemotherapies, could potentially slow or even prevent the development of chemotherapy resistance, improving the outlook for this aggressive form of breast cancer.

The research was conducted at Vanderbilt-Ingram Cancer Center and appears in the journal Cell Metabolism. The research was supported by the Susan G. Komen for the Cure Foundation, the Breast Cancer Research Foundation, a National Institutes of Health Breast Cancer SPORE grant, and a Vanderbilt-Ingram Cancer Center Support Grant.

The Simmons Cancer Center at UT Southwestern is one of 49 NCI-designated Comprehensive Cancer Centers in the U.S. and the only one in North Texas. It is also one of 30 U.S. cancer research centers to be designated by the National Cancer Institute as a National Clinical Trials Network Lead Academic Site.

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.

By Decoding How HPV Causes Cancer, Researchers Find a New Potential Treatment Strategy

A study that teases apart the biological mechanisms by which human papillomaviruses (HPV) cause cancer has found what researchers at Georgetown University Medical Center say is a new strategy that might provide targeted treatment for these cancers.

HPVs are responsible for the majority of cervical cancer and a substantial portion of head and neck and anal cancers, but therapy available to date is surgery and non-specific chemotherapy.

The new study, published Oct. 2 in the journal Oncotarget, found that E6, an oncoprotein produced by the virus, interacts with several other molecules in host cells in a manner that ensures infected cells cannot die. If they are immortal and continue to multiply, cancer develops.

“There is no targeted treatment now for these cancers since German virologist Harald zur Hausen, PhD, discovered in 1983 that HPV can cause cervical cancer. Recently, the numbers of HPV-linked head and neck cancers have increased in the U.S. Now we have a chance to develop and test a very specific, potentially less toxic way to stop these cancers,” says the study’s lead author, Xuefeng Liu, MD, associate professor of pathology at Georgetown University Medical Center.  Liu is director of Telomeres and Cell Immortalization for the medical center’s Center for Cell Reprogramming.

Liu and his team have previously found that the HPV E6 oncoprotein interferes with the well-known p53 tumor suppressor to increase telomerase activity that extends the life span of infected cells. A telomerase is a protein that allows a cell to divide indefinitely when it would have stopped after a certain number of divisions.

In this study, researchers found that E6 also interacts with myc, a protein produced by the Myc gene, which controls gene expression in all healthy cells. They concluded that telomerase activity is dependent on E6-myc proteins hooking on to each other.

This means, says Liu, that designing a small molecule that stops E6 from joining up with myc should shut down persistent activation of telomerase. A small molecule could bind to E6 in the same spot that myc would, or bind on to myc in the same spot that E6 would, thus preventing an E6-myc complex.

“This small molecule would not be toxic to all normal cells or, importantly, to master stem cells, because myc would not be affected,” says Liu. “It could be a unique treatment, targeted specifically to HPV cancers.”

Georgetown researchers are now working on a prototype chemical to interfere with E6/Myc binding.

New research on probiotics in the prevention and treatment of colon cancer

In an innovative approach to colorectal cancer (CRC) prevention and treatment, scientists are studying ways to replace missing metabolites in patients prone to gut inflammation and CRC. A new study in The American Journal of Pathology describes how administration of histamine-producing gut microbes to mice lacking the enzyme histidine decarboxylase (HDC) reduced inflammation and tumor formation. These results suggest that alteration of the gut microbiome with probiotics may become a new preventative or therapeutic strategy for patients at risk for inflammatory bowel disease (IBD)-associated CRC.

“We are on the cusp of harnessing advances in microbiome science to facilitate diagnosis and treatment of human disease,” explained James Versalovic, MD, PhD, pathologist-in-chief at Texas Children’s Hospital, and Milton J. Finegold Professor of pathology & immunology at Baylor College of Medicine (Houston). “By simply introducing microbes that provide missing life substances, we can reduce the risk of cancer and supplement diet-based cancer prevention strategies.”

Researchers conducted a series of experiments using mice that were deficient in HDC, the enzyme required to convert histidine to histamine. Experimental mice were orally administered the probiotic Lactobacillus reuteri 6475, which is known to possess the histidine decarboxylase gene (hdc+) and is able to convert histidine to histamine; control animals received a placebo. The probiotic was administered both before and after the mice received a single dose of a colonic carcinogen (azoxymethane) plus an inflammation-inducing chemical (DSS) to induce tumor formation. Fifteen weeks later, the mice were sacrificed and the tissues removed for study.

The probiotic increased expression of bacterial HDC and amounts of histamine in the colons of the mice. Using positron emission tomography (PET) to visualize the tumors, control-treated mice showed evidence of tumors and increased glucose uptake in colon walls. In contrast, mice administered the probiotic had fewer and smaller tumors and significantly diminished areas of glucose uptake.

Inactive L. reuteri strains (those deficient in HDC activity) did not provide protective effects. These mice showed increased numbers of “hot spots” indicative of tumor formation and increased abdominal glucose uptake.

The active probiotic also reduced inflammation induced by the carcinogen plus DSS, as indicated by suppressed pro-inflammatory cytokine gene expression (i.e., those encoding KC, interleukin (IL)-22, IL-6, tumor necrosis factor (TNF), and IL-1α) and reduced cytokine concentrations in plasma (i.e., KC, IL-22, and IL-6). The active probiotic also counteracted an increase in immature myeloid cells induced by the carcinogen. According to Dr. Versalovic, “These observations are consistent with the conclusion that histamine-generating probiotic L. reuteri may attenuate AOM+DSS-induced colon carcinogenesis, at least in part, via enhanced maturation of circulating myeloid cells and concomitant reduction of pro-inflammatory cytokines.”

The role of histamine in human cancer is still unclear. However, when investigators analyzed data obtained from 2,113 CRC patient samples taken from 15 datasets, results showed better survival in patients with elevated patterns of HDC and histamine receptor gene expression. These findings indicate that histamine-generating probiotics, in the presence of sufficient protein (L-histidine) intake, may improve outcomes for patients with sporadic and IBD-associated CRC.

“Our results suggest a significant role for histamine in the suppression of chronic intestinal inflammation and colorectal tumorigenesis. We have also shown that cells, both microbial and mammalian, can share metabolites or chemical compounds that together promote human health and prevent disease,” said Dr. Versalovic.

Cell Surface Protein May Offer Big Target in Treating High-Risk Childhood Cancers

Oncology researchers studying high-risk children’s cancers have identified a protein that offers a likely target for immunotherapy–harnessing the immune system in medical treatments. In cell cultures and animal models, a potent drug attached to an antibody selectively zeroes in on cancer cells without harming healthy cells.

“We have built a strong foundation for developing a completely new and hopefully much less toxic treatment for neuroblastoma, the most common cancer in infants,” said study supervisor John M. Maris, MD, a pediatric oncologist at Children’s Hospital of Philadelphia (CHOP). “Furthermore, our findings may also lend support to the development of other immune-based therapies, such as CAR T-cells, in children with multiple aggressive cancers in addition to neuroblastoma.”

Maris, along with study leader and first author Kristopher R. Bosse, MD, and colleagues published their study today in Cancer Cell, which featured their findings as the cover story.

Neuroblastoma is a cancer of the developing peripheral nervous system that usually occurs as a solid tumor in a child’s chest or abdomen, and is the most common cancer in infants. It accounts for a disproportionate share of cancer deaths in children. Over decades, CHOP clinicians and researchers have built one of the world’s leading programs in neuroblastoma.

The study team used sophisticated sequencing tools to first discover molecules that are much more commonly found on the surface of neuroblastoma cells than on normal cells. “Our rationale was to identify a cell-surface molecule that an immune-based therapy could target without damaging healthy tissues,” said Bosse. “Using this approach, we identified a protein called glypican-2, or GPC2.” GPC2 is one of a family of glypicans—cell-surface proteins that interact with growth factors and cell surface receptors, influencing many intracellular signaling pathways important in development and cancer.

In addition to GPC2’s presence on neuroblastoma cells, the study team also found that GPC2 is necessary for a neuroblastoma tumor to proliferate. Both of those facts implied that a compound that acted against GPC2 might kill cancer cells, spare healthy cells, and limit the possibility of these tumors developing “immune escape” mechanisms, in which cancer cells resist an immunotherapy by shedding the target. “Given GPC2’s critical role in the growth of neuroblastomas, we hope that tumors will not be able to simply downregulate this protein in order to escape recognition by our immunotherapies that target GPC2,” said Bosse.

After pinpointing GPC2 as a very promising target for therapy, the researchers next worked with their colleagues at the National Cancer Institute to search for a weapon. They developed an antibody-drug conjugate (ADC) called D3-GPC2-PBD, which combined a very specific antibody that recognizes GPC2 with a potent chemotherapy drug that is internalized specifically by cancer cells. The drug payload damages DNA in tumors, while sparing healthy tissues from its toxic effects.

In cell cultures and mouse models of neuroblastoma, the ADC robustly killed neuroblastoma cells with no discernible toxicity to normal cells. “These findings establish that this type of immunotherapy could be potentially safe and effective against neuroblastoma,” said Maris. “Our next steps will be to further evaluate this ADC and also develop other immune-based therapies directed against GPC2. Because other glypicans in addition to GPC2 are overexpressed in other childhood cancers, it may also be possible to apply this approach across various types of high-risk pediatric cancers.”

Accelerating the Development of Next-Generation Cancer Therapies

To accelerate the development of next-generation cancer therapies, the Gene Editing Institute of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System has agreed to provide genetically modified cell lines to Analytical Biological Services, Inc. (ABS) of Wilmington, Delaware.

Under a three-year agreement, the Gene Editing Institute will act as sole provider of gene editing services and genetically modified cell lines to ABS for replication, marketing and distribution to leading pharmaceutical and biomedical research companies worldwide.

“This agreement with ABS will speed the progress in the discovery of effective cancer therapies and accelerate the path to prevention, diagnosis and treatment of many forms of cancer,” said Nicholas J. Petrelli, M.D., the Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System.

“This partnership greatly enhances our capability to provide the highest quality genetically engineered cells for drug discovery,” said ABS President and CEO Charles Saller, Ph.D. “Our partners at the Gene Editing Institute are advancing molecular medicine, and their expertise adds a new dimension to our efforts to speed up drug discovery.”

“One goal of The Gene Editing Institute is to develop community partnerships that can advance translational cancer research,” said Eric Kmiec, Ph.D., founder and director of the Gene Editing Institute. “The Gene Editing Institute is driving innovation in gene engineering, and ABS has the know-how to grow and expand the cells in sufficient quantities, as well as to market them to pharmaceutical and biotechnology clients for drug screening and research.”

The Gene Editing Institute is a worldwide leader in the design of the tools that scientists need to manipulate and alter human genetic material easier and more efficiently than ever before. Scientists at the Gene Editing Institute have designed and customized an expanding tool-kit for gene editing, including the renowned CRISPR-Cas9 system, to permanently disrupt or knock out genes, add or knock in DNA fragments and create point mutations in genomic DNA. Last year, scientists at the Gene Editing Institute described in the journal Scientific Reports how they combined CRISPR and short strands of synthetic DNA to greatly enhance the precision and reliability of the CRISPR gene editing technique. Called Excision and Corrective Therapy, or EXACT, this new tool acts as both a Band-Aid and a template during gene mutation repairs.

Genetically modified cells can help advance cancer research. By inactivating a single gene, scientists can test if it affects tumor formation or somehow alters the response to cancer therapies. Similarly, inserting a gene into a cell can produce a gene product that is a target for potential new drugs.

“Gene editing and the CRISPR technology is having a major impact on anticancer drug development because it allows us to validate the target of the candidate drug,” said Dr. Kmiec. “Pharmaceutical companies want to use gene editing tools to identify new targets for anti-cancer drugs and to validate the targets they already have identified.”

The Delaware BioScience Association helped connect the Gene Editing Institute with ABS. “The collaborative agreement between the Gene Editing Institute and ABS exemplifies the power of building a strong biotech community, flourishing further innovation, and keeping businesses engaged and thriving in the state of Delaware,” said Helen Stimson, president and CEO of The Delaware BioScience Association. “The Delaware BioScience Association is committed to fostering meaningful relationships, such as this one, among its members, and establishing strategic partnerships that bolster the state’s innovation economy,” she said.

“This is one of those times when the forces of nature align to bring two perfectly matched skill sets together,” said Dr. Kmiec. “There is no question that our collaboration with ABS will accelerate the pace of drug discovery around the world.”

About The Gene Editing Institute

The Gene Editing Institute of Christiana Care Health System’s Helen F. Graham Cancer Center & Research Institute is unlocking the genetic mechanisms that drive cancer that can lead to new therapies and pharmaceuticals to revolutionize cancer treatment. Gene editing in lung cancer research has already begun setting the stage for clinical trials.

The Gene Editing Institute is integrated into the Molecular Screening Facility at The Wistar Institute in Philadelphia, PA, where its innovative gene-editing technologies are available to research projects at Wistar and to external users. Working with Wistar scientists, the Gene Editing Institute has begun research to conduct a clinical trial in melanoma. With funding from the National Institutes of Health, the Gene Editing Institute is partnering with A.I. duPont/Nemours to develop a gene editing strategy for the treatment of sickle cell anemia and leukemia. Under a grant from the U.S.–Israel Binational Industrial Research & Development Foundation, the Gene Editing Institute is working with Jerusalem-based NovellusDx to improve the efficiency and speed of cancer diagnostic screening tools. This work could lead to earlier identification of genetic mechanisms responsible for both the onset and progression of many types of cancers and the development of individualized therapeutics.

Gene Editing Institute scientists also provide instruction in the design and implementation of genetic tools. Partnerships with Bio-Rad Inc. and the Delaware Technical and Community College are producing gene editing curricula and teacher training workshops for both community colleges and secondary schools.