Enzyme Inhibitor Combined with Chemotherapy Delays Glioblastoma Growth

 In animal experiments, a human-derived glioblastoma significantly regressed when treated with the combination of an experimental enzyme inhibitor and the standard glioblastoma chemotherapy drug, temozolomide.

The regression seen in this combination therapy of temozolomide and the inhibitor SLC-0111 — which targets the enzyme carbonic anhydrase 9, or CA9 — was greater than that seen with either SLC-0111 or temozolomide alone, says research leader Anita Hjelmeland, Ph.D., assistant professor in the Department of Cell, Developmental and Integrative Biology at the University of Alabama at Birmingham.

“Our experiments strongly suggest that a strategy to target a carbonic anhydrase that is increased in glioblastoma, CA9, will improve temozolomide efficacy,” Hjelmeland said. “We believe the drug combination could improve patient outcomes in glioblastomas sensitive to chemotherapy.”

Glioblastoma is the most common primary brain tumor seen in adults. Half of the tumors recur less than seven months after undergoing the standard treatment of surgery, temozolomide and radiation. The median survival after diagnosis of this deadly cancer is 12 to 14 months. Thus, new approaches to therapy are urgently needed.

Solid tumors like glioblastoma create microenvironments within and around themselves. A common condition is hypoxia, a shortage of oxygen as the tumor outgrows its blood supply. Tumor cells shift to making their energy through glycolysis, a method of metabolism that does not require oxygen. Glycolysis, in turn, changes the acid-base balance at the tumor — the extracellular space becomes more acidic and the tumor cell interiors become more alkaline, adapting to this change.

In the face of this hypoxia and acid stress, tumor cells over-produce CA9, a membrane enzyme that converts carbon dioxide and water to bicarbonate and protons. This reaction aids maintenance of the altered acid-base balance in the tumor microenvironment.

Thus, CA9 is a possible therapeutic target, and the inhibitor SLC-0111 shows more than 100-fold specificity against CA9, versus two other forms of human carbonic anhydrases, CA1 or CA2. Furthermore, collaborators on this project have previously shown that SLC-0111 exhibits effectiveness against breast cancer xenografts in animals. SLC-0111 has been tested in Phase I clinical safety trials sponsored by Welichem Biotech Inc. in Canada for patients with advanced solid tumors.

The research team led by Hjelmeland and co-first authors Nathaniel Boyd, Ph.D., and Kiera Walker, both working in Hjelmeland’s UAB lab, studied glioma cells in cell-culture that were derived from an aggressive pediatric primary glioblastoma and from an adult recurrent tumor. The researchers also studied the tumor in mice, using the adult recurrent glioblastoma.

One reason for recurrence of glioblastoma is a therapeutically resistant sub-population of glioma cells known as brain tumor initiating cells. Part of the focus of the Hjelmeland team was to look at the effect of the combination therapy on that subset of glioblastoma cells.

The researchers found that the combined treatment with temozolomide and SLC-0111 in cell culture experiments: 1) reduced glioblastoma cell growth, 2) induced arrest of the cell-division cell cycle by creating breaks in DNA, 3) shifted the tumor metabolism and intracellular acid-base balance by decreasing metabolic intermediates, and 4) inhibited enrichment of brain tumor initiating cells.

In experiments with mice, the combined treatment with temozolomide and SLC-0111: 1) delayed tumor growth of a patient-derived, recurrent glioblastoma xenograft implanted beneath the skin of immunocompromised mice, as compared to temozolomide alone, and 2) improved survival of the mice when the xenograft was implanted in the brain, a placement that more closely models glioblastoma in patients.

“Clinical trials in glioblastoma often initiate with patients that have a tumor recurrence, and we have demonstrated in vivo efficacy for SLC-0111 with temozolomide in a recurrent glioblastoma,” the researchers wrote in their study, published in JCI Insight. “Therefore, our data strongly suggest the translational potential of SLC-0111 for glioblastoma therapy.”

“With funds from the Southeastern Brain Tumor Foundation,” Hjelmeland said, “we continue to determine whether there are subtypes of glioblastomas that are most likely to respond to combinatorial therapy.

Two New Breast Cancer Genes Emerge from Lynch Syndrome Gene Study

The findings suggest that genetic screening for breast cancer should be expanded to include MSH6 and PMS2

Researchers at Columbia University Irving Medical Center and NewYork-Presbyterian have identified two new breast cancer genes. Having one of the genes—MSH6 and PMS2—approximately doubles a woman’s risk of developing breast cancer by age 60.

The study, in collaboration with GeneDx, a genetic testing company, was published online today in Genetics in Medicine.

The two genes were previously known to cause Lynch syndrome, an inherited condition that raises the risk of colorectal, ovarian, stomach, and endometrial cancer. Lynch syndrome is the most common inherited cause of colorectal cancer, accounting for about 3 percent of newly diagnosed cases. One in 440 Americans has a gene variant that causes Lynch syndrome.

Researchers had suspected that Lynch syndrome genes may also cause breast cancer. Some studies had found a link, whereas others had not.

“People with Lynch syndrome aren’t thinking they may also be at risk for breast cancer,” said Wendy Chung, MD, PhD, the Kennedy Family professor of pediatrics (in medicine) at Columbia University Irving Medical Center, clinical geneticist at NewYork-Presbyterian/Columbia, and the study’s senior author. “Given the fact that genomic analysis is becoming more common in patients with a personal or family history of cancer, we have an opportunity to do more targeted breast cancer screening in women who carry any of the genes associated with risk for this disease.”

The researchers analyzed a database of more than 50,000 women who had undergone multi-gene hereditary cancer testing between 2013 and 2015. Of these, 423 women had a mutation in one of the four genes that cause Lynch syndrome: MLH1, MSH2, MSH6, and PMS2.

Additional analyses revealed that women with a mutation in two specific Lynch syndrome genes—MSH6 and PMS2—had a two-fold higher risk of breast cancer compared to women in the general population.

Based on the incidence of cancer in the study population, the researchers calculated that about 31 to 38 percent of women with cancer-causing MSH6 and PMS2 variants will develop breast cancer, compared to around 15 percent of women in the general population.

“The new study suggests MSH6 and PMS2 should be added to the list of genes to screen for when there is a history of breast cancer,” said Dr. Chung, who is also director of the clinical genetics program at NewYork-Presbyterian/Columbia. “Screening for these genes also would give these families potentially life-saving information to prevent colon cancer by encouraging individuals with the genes to increase the frequency of their colonoscopies.”

Currently, testing for Lynch syndrome genes is generally only done when someone has a personal or family history of colon or uterine cancer.

Dr. Chung added, “Given that Lynch syndrome is not rare in the general population, this finding has the potential to impact tens of thousands of people in the U.S. and could change standard practice related to one of the most common cancer predisposition syndromes.”

The study is titled, ‘MSH6 and PMS2 Germline Pathogenic Variants Implicated in Lynch Syndrome are Associated with Breast Cancer.’

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

Placental Cells Significantly Inhibit Cancer Cell Growth in Newly Published Study

According to the peer-reviewed article in the journal Scientific Reports, placenta-derived cells called PLX cells, exhibit a strong inhibitory effect on various lines of breast, colorectal, kidney, liver, lung, muscle and skin cancers. The research was conducted over more than two years by Pluristem Therapeutics, Inc., a Haifa-based biotechnology company.

The article titled “Human Placental-Derived Adherent Stromal Cells Co-Induced with TNF‑a and IFN‑g Inhibit Triple-Negative Breast Cancer in Nude Mouse Xenograft Models” is based on studies which examined the effect of Pluristem Therapeutic‘s PLX cells that had been induced with tumor necrosis factor alpha (TNF-a) and interferon-gamma (IFN-g), on the proliferation of over 50 lines of human cancerous cells. The induction of the cells was carried out by adjusting their manufacturing process in order to transiently alter their secretion profile.

Data from the first study showed that the modified PLX cells exhibited an anti-proliferative effect on 45% of the tested cancer cell lines, with a strong inhibitory effect on various lines of breast, colorectal, kidney, liver, lung, muscle and skin cancers. Comprehensive bioinformatics analysis identified common characteristics of the cancer cell lines inhibited by PLX cells. This knowledge could potentially be used in the future for screening patients’ tumors to identify those patients most likely to show a positive response to treatment with PLX cells.

Based on these promising results, Pluristem conducted a pre-clinical study of female mice harboring human triple negative breast cancer (TNBC). TNBC is an aggressive form of breast cancer that does not respond to standard hormonal therapy due to a lack of estrogen and progesterone receptors. Current treatment for TNBC consists of a combination of surgery, radiation therapy, and chemotherapy, and yet the prognosis remains poor for patients with this type of breast cancer. In this study, weekly intramuscular (IM) injections of the induced PLX cells produced a statistically significant reduction (p= 0.025) in mean tumor size in the treated group compared with the untreated group, with 30% of the treated mice exhibiting complete tumor remission. In addition, a statistically significant reduction (p=0.003) was seen in the percentage of proliferating tumor cells as well as in the level of blood vessels within the tumors.

“The findings of this study published in a peer-reviewed journal are the outcome of over two years of research as well as the vast knowledge of PLX cell properties we have developed over the last 10 years. We believe the findings show promise for the utilization of our induced PLX cells in slowing and reversing the growth of cancer cells, particularly for some cancers that don’t have viable treatment options,” stated Zami Aberman, Chairman and Co-CEO of Pluristem. “The findings also confirm the effectiveness of IM administration and support a mechanism of action involving immunomodulation and inhibition of angiogenesis and cell proliferation in cancerous conditions. Our unique patented manufacturing platform allows us to alter our cells’ secretion profile in correlation with the targeted cancer cells, which may open new possibilities in the field of oncology to treat solid tumors and may also offer new paths to help millions of patients around the world. As in immunotherapy technology, PLX cells potentially have the ability to communicate with the body and to secrete biological components that enhance regeneration processes and support the body in fighting cancer cells.”

Pluristem has filed patent applications relating to the technology for the induction of PLX cells and the use of these cells for the treatment of cancer.

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.”

Researchers Seek Blood Test for Early Lung Cancer Detection

Researchers at Rush University Medical Center are trying to answer that question by working to develop a blood test for early detection of lung cancer. National Institutes of Health awarded this endeavor a two-year $275,000 grant on Jan. 1.

The availability of a simple and cost-effective blood test could change early detection of lung cancer, which is often undiagnosed until symptoms become apparent in a more serious, advanced stage of the disease.

“Our goal is to improve the way lung cancer is diagnosed using a simple blood test to detect the disease earlier and reduce the number of late-stage diagnoses,” said biochemist Jeffrey A. Borgia, PhD. “We are aiming to identify those who are at a higher risk by looking for a specific ‘signature’ of cancer-specific molecules (or biomarkers) in the blood.

“Currently there are screening guidelines for those who are at risk — people who have a history of smoking and are 55 to 80 years old — but what about a nonsmoking young person who gets lung cancer?”

According to the American Cancer Society, as many as 20 percent of the people who die from lung cancer in the United States every year have never smoked or used any other form of tobacco. This translates to about 30,000 Americans in 2017.

Blood test would improve on and complement CT screenings

Currently, people at risk for lung cancer are advised to receive a low-dose computed tomography (CT) scan of their lungs to detect early-stage cancers.

“It is an effective screening tool, but most of the nodules we identify with CT scanning will turn out to be benign,” said Dr. Christopher Seder, a thoracic surgeon at Rush. “We are trying to develop a better way to determine whether the nodule is malignant or not.”

Also, while low-dose CT scanning currently is the best method for catching lung cancer early, the established guidelines for screening exclude many people who may still be diagnosed with the disease.

“The blood test ideally could be used as a detection method that will complement current CT imaging technology,” Borgia said.

Biomarkers are key to cancer test

Cancer cells release a series of proteins and other biomolecules into the bloodstream that are unique to the type of cancer, known as biomarkers.

Using one of the world’s largest institutional repositories of blood and tissue samples from patients with benign and malignant thoracic tumors at Rush, Borgia’s team has identified several biomarkers in the blood that may be able to identify non-small cell lung cancer with about 90 percent accuracy.

Thanks to the cell samples from patients — about 10 percent of whom fall outside current CT screening criteria — the team also is searching for biomarkers that could lead to a “prescreening” blood test designed to detect additional populations that might benefit from CT screening but do not meet current criteria, outlined above.

Rush University Medical Center has been on the leading edge of the lung cancer CT screening and lung cancer treatment. Rush is an American College of Radiology-designated screening center as well as a Lung Cancer Alliance Screening Center of Excellence.

Rush’s preventive low-dose screening program, created in 2015, resulted in more than 3 percent cancer diagnoses found at earlier stages than when lung cancers are typically found. For these early-stage cancers, Dr. Michael Liptay and his thoracic surgical colleagues at Rush were able to perform minimally invasive procedures that gave these patients a better chance at survival.

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.

Researchers Map Molecular Interaction That Prevents Aggressive Breast Cancer

Researchers in Italy have discovered how specific versions of a protein called Numb protect the key tumor suppressor p53 from destruction. The study, which will be published December 21 in the Journal of Cell Biology, suggests that the loss of these particular Numb proteins makes breast cancers more aggressive and resistant to chemotherapy, but points the way toward new therapeutic approaches that could improve patient outcome by preserving p53 levels.

Cells produce several alternative isoforms of Numb by differentially processing, or splicing, the mRNA encoding Numb to include or exclude specific regions of the protein. How this alternative splicing affects Numb’s various functions remains unclear.

In mammary gland stem cells, for example, Numb binds and inhibits an enzyme called Mdm2, preventing it from targeting p53 for degradation. Numb therefore stabilizes p53 and allows this tumor suppressor protein to limit stem cell proliferation. If the stem cells lose Numb, however, p53 levels plunge and the cells proliferate uncontrollably, leading to the emergence of cancer stem cells that drive the growth of breast tumors. Cancer cells that lack p53 are also more resistant to chemotherapy drugs that kill cells by damaging their DNA.

A team of researchers based in Milan set out to identify how Numb binds to Mdm2. The team was led by Pier Paolo Di Fiore of the FIRC Institute for Molecular Oncology (IFOM), the European Institute of Oncology (EIO), and The University of Milan, as well as Salvatore Pece of EIO and The University of Milan and Marina Mapelli of EIO.

The researchers found that a small region of Numb—comprising just 11 amino acids—is responsible for binding and inhibiting Mdm2. This region is present in Numb isoforms 1 and 2 but excluded from isoforms 3 and 4. Accordingly, depleting Numb-1 and -2 from breast cancer cells reduced the levels of p53, whereas depleting Numb-3 and -4 had no effect.

The researchers then compared tumor cells isolated from multiple different breast cancer patients and found that cells expressing lower amounts of Numb-1 and -2 were more resistant to the chemotherapy agent cisplatin. Treating these cells with an Mdm2 inhibitor boosted p53 levels and increased the cells’ sensitivity to cisplatin.

“We reasoned that breast cancers displaying reduced levels of Numb-1 and -2, being resistant to genotoxic agents, might also display poorer disease outcome,” explains Pece.

The team therefore analyzed the case history of 890 breast cancer patients and found that low Numb-1 and -2 levels correlated with an increased risk of aggressive, metastatic disease, particularly for the luminal subtype of breast cancers, which tend to retain a normal, functional copy of the p53 gene.

“Our results show how Numb splicing specifically impacts the regulation of p53 and breast cancer prognosis,” Mapelli says.

“We hope that it will be possible to exploit the knowledge of the molecular basis of the Numb–Mdm2 interaction in the rational design of molecules that can mimic the crucial region in Numb and inhibit Mdm2 to relieve p53 dysfunction in Numb-defective breast cancers,” Di Fiore says.

Harnessing Sperm to Treat Gynecological Diseases

Delivering drugs specifically to cancer cells is one approach researchers are taking to minimize treatment side effects. Stem cells, bacteria and other carriers have been tested as tiny delivery vehicles. Now a new potential drug carrier to treat gynecological conditions has joined the fleet: sperm. Scientistsreport in the journal ACS Nano that they have exploited the swimming power of sperm to ferry a cancer drug directly to a cervical tumor in lab tests.

Creating an effective way to target cancer cells with drugs is challenging on multiple fronts. For example, the drugs don’t always travel deeply enough through tissues, and they can get diluted in body fluids or sidetracked and taken up by healthy organs. To get around these issues, scientists have turned in some cases to loading pharmaceuticals into bacteria, which can effectively contain drug compounds and propel themselves. The microbes can also be guided by a magnetic field or other mechanism to reach a specific target. However, the body’s immune system can attack the microbes and destroy them before they reach their target. Looking for another self-propelled cell as an alternative drug carrier to bacteria, Mariana Medina-Sánchez and colleagues at the Leibniz Institute for Solid State and Materials Research—Dresden (IFW Dresden) turned to sperm.

The researchers packaged a common cancer drug, doxorubicin, into bovine sperm cells and outfitted them with tiny magnetic harnesses. Using a magnetic field, a sperm-hybrid motor was guided to a lab-grown tumor of cervical cancer cells. When the harness arms pressed against the tumor, the arms opened up, releasing the sperm. The sperm then swam into the tumor, fused its membrane with that of a cancer cell, and released the drug. When unleashed by the thousands, drug-loaded sperm killed more than 80 percent of a cancerous ball while leaking very little of their payload en route. Further work is needed to ensure the system could work in animals and eventually humans, but researchers say the sperm motors have the potential to one day treat cancer and other diseases in the female reproductive tract.

Tumor Mutational Burden and Response to Immune Checkpoint Therapy

Predicting how patients will respond to anti-cancer therapies can be vital in informing clinical decisions and improving treatment outcome.  Researchers at Rutgers Cancer Institute of New Jersey examined an association between mutational burden and response to immune checkpoint therapy in several cancer types and found that a mutational burden threshold exists in eight cancers that predict response to an immune checkpoint blockade.

The work’s co-corresponding authors Shridar Ganesan, MD, PhD, associate director for translational science and chief of molecular oncology at Rutgers Cancer Institute, the Omar Boraie Chair in Genomic Science, and  associate professor of medicine and pharmacology at Rutgers Robert Wood Johnson Medical School; and  Rutgers Cancer Institute research member Gyan Bhanot, PhD, professor of molecular molecular biology and biochemistry and professor of physics in the School of Arts and Sciences at Rutgers University, along with lead author Anshuman Panda, MPhil, a Rutgers Physics Department graduate student, share more about the work, published in the December 7 online edition of JCO Precision Oncology (DOI: 10.1200/PO.17.00146): 

Q:  Why is this topic important to explore?

A:  Immune checkpoint blockade therapies have recently been in the news as novel ways to target a variety of cancers. However, these therapies are very expensive and have significant side effects. Furthermore, not all patients respond to such therapy. It is therefore important to identify markers of response for these therapies in relation to the various cancer types to improve treatment efficacy.

Q:  Describe the research and your findings.

A:  We analyzed mutation and gene expression data for more than 9,000 tumor samples from 33 solid tumor types using data from The Cancer Genome Atlas (TCGA) to test whether a high mutational burden is associated with a signature of a blocked immune response. We found that such a mutational burden threshold, which we call the iCAM threshold, exists in eight solid tumors, namely melanoma, lung, colon, stomach adenocarcinoma, endometrial, bladder-urothelial and cervical cancer, and ER+HER2− breast cancer. The efficacy of this threshold in predicting response to anti-immune checkpoint blockade therapy was validated in published data for melanoma, colon and lung adenocarcinoma as well as in a large prospective cohort of 113 samples from Rutgers Cancer Institute and the Vanderbilt Ingram Cancer Center. We also showed that the iCAM threshold is identifiable with high accuracy using routine sequencing assays, such as the FoundationOne and StrandAdvantage assays. Finally, we find that iCAM+ and iCAM- tumors have very distinct mutational profiles, suggesting these are distinct diseases driven by different biological pathways.

Q:  What are the implications for future treatments with checkpoint therapy drugs?

A: The iCAM threshold provides a simple, cost-effective way to identify patients likely to respond to immune checkpoint therapy in eight cancer types using routine sequencing assays currently used in clinical practice.

Researchers repurpose immune-activating cytokine to fight breast cancer

The most lethal form of breast cancer could have a new treatment option, according to new research out of the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine. In the Proceedings of the National Academy of Sciences, researchers showed triple-negative breast cancer cells are highly vulnerable to interferon-β–a potent antimicrobial that also activates the immune system. The new study shows interferon-β impairs breast cancer cells’ ability to migrate and form tumors. The study also suggests interferon-β treatment could improve outcomes for certain breast cancer patients.

“We demonstrate that interferon-β reverses some of the more aggressive features of triple-negative breast cancer, which are responsible for metastasis and therapy-failure,” said Mary Doherty, first author and pathology graduate student at Case Western Reserve School of Medicine. “Moreover, we found that evidence of interferon-β in triple-negative breast cancer tumors correlates with improved patient survival following chemotherapy.”

Doherty’s advisor, Mark Jackson, PhD, associate professor of pathology and associate director for training and education, Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine, is senior author on the study. The study team also included researchers from Cleveland Clinic Lerner Research Institute, University Hospitals Cleveland Medical Center, Stanford University School of Medicine, and other members of the Case Comprehensive Cancer Center.

Triple-negative breast cancer is one of the deadliest, most aggressive forms of breast cancer. It spreads rapidly and is resistant to many available chemotherapies. Even when therapies appear successful, tumors often recur. Said Doherty, “While chemotherapy kills the majority of tumor cells, it fails to eliminate a sub-set of cancer cells, called cancer stem cells. The survival of these cancer stem cells following therapy is believed to be responsible for therapy failure in patients.”

The new study showed interferon-β directly targets cancer stem cells. In laboratory dishes, regular treatments of interferon-β kept triple-negative breast cancer stem cells from migrating–the first step in metastasis. Even two days after stopping treatment, dishes with interferon-β added had approximately half the number of migrating stem cells as controls. Cells exposed to interferon-β also lacked markers characteristic of early tumors and failed to aggregate into tumor-like spheres.

The researchers validated their laboratory findings using a breast cancer tissue database. They found elevated interferon-β levels in breast tissue correlated with extended patient survival and lower cancer recurrence rates. Patients with higher interferon-β levels in their breast tissue were approximately 25 percent less likely to experience a recurrence than those with low levels. The authors concluded that interferon-β plays a “positive, critical role” in triple-negative breast cancer outcomes.

The researchers are now studying how interferon-β may modulate the immune system to carry out its anti-cancer effects. They also plan to conduct clinical trials evaluating interferon-β as a new therapeutic option for triple-negative breast cancer, either alone or in combination with traditional chemotherapy. Such a study could require novel methods to deliver interferon-β to breast cancer tumors. Said Doherty, “Our future studies will examine improved methods of interferon-β delivery to the tumor site incorporating nanoparticle technology.” Together, the studies could expand treatment options for patients suffering from drug-resistant breast cancers.

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.

2-Drug Combination May Boost Immunotherapy Responses in Lung Cancer Patients

Johns Hopkins Kimmel Cancer Center researchers and colleagues have identified a novel drug combination therapy that could prime nonsmall cell lung cancers to respond better to immunotherapy. These so-called epigenetic therapy drugs, used together, achieved robust anti-tumor responses in human cancer cell lines and mice.

During the study, published Nov. 30, 2017, in the journal Cell, a team of researchers led by graduate student Michael Topper; research associate Michelle Vaz, Ph.D.; and senior author Stephen B. Baylin, M.D., combined a demethylating drug called 5-azacytidine that chemically reignites some cancer suppressor genes’ ability to operate, with one of three histone deacetylase inhibitor drugs (HDACis). The HDACis work against proteins called histone deacetylases that are involved in processes, such as cell copying and division, and can contribute to cancer development. The combination therapy triggered a chemical cascade that increased the attraction of immune cells to fight tumors and diminished the work of the cancer gene MYC. Based on these findings, investigators have launched a clinical trial of the combination therapy in patients with advanced, nonsmall cell lung cancer.

The development of therapeutic approaches for patients with lung cancer has been a critical medical need, says Baylin, the Virginia and Daniel K. Ludwig Professor of Cancer Research at the Kimmel Cancer Center. While immune checkpoint therapy has been “a tremendous step forward, less than half of patients with lung cancer have benefited to date,” he says.

“In our study, the two-drug epigenetic therapy combination worked exceedingly well, even before putting in the immune checkpoint inhibitors,” Baylin says. “In animal models of lung cancer, the two agents either prevented cancer from emerging or blunted the effects of more aggressive cancers. In both scenarios, a large component of the results involved an increase in immune recognition of the tumors.”

In a series of experiments, researchers studied the combination of 5-azacytidine with the HDACis entinostat, mocetinostat or givinostat in human cancer cell lines and in mouse models of nonsmall cell lung cancers. The treatments were found to alter the tumor microenvironment. In cancer cell lines, 5-azacytidine worked against the cancer gene MYC, causing down regulation of the entire MYC signaling program. Adding the HDACis further depleted MYC, and together the drugs subsequently caused actions that prevented cancer cell proliferation, simultaneously attracted more immune system T cells to the area of the tumor and activated these cells for tumor recognition.

In mouse models, the strongest response was observed when using 5-azacytidine plus givinostat. In one mouse model with a mutant form of nonsmall cell lung cancer, this drug combination given for three months yielded prevention of benign, precursor tumors from becoming cancers and caused 60 percent reduction of overall area of benign tumor appearance in the lungs. By contrast, a group of mice with the same form of lung cancer that were given a mock treatment universally developed large, cancerous lesions in the lungs.

In a second model of mice with established, aggressive, nonsmall cell lung cancer, treatment with an alternating schedule of 5-azacytidine with givinostat and of 5-azacytidine with mocetinostat not only reduced the growth of established, rapidly growing primary tumors but also dramatically reduced metastatic occurrence.

Baylin and colleagues at Memorial Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia have started a phase I/Ib clinical trial to evaluate if giving mocetinostat with a 5-azacytidinelike drug called guadecitabine can boost immune checkpoint therapy responses in patients with advanced, nonsmall cell lung cancers. The trial is part of the Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team and is funded by Merck through the Stand Up To Cancer  (SU2C) Catalyst program, an initiative led by SU2C to bring innovative cancer treatments to patients quickly. Matthew Hellmann, M.D., an author on the paper, will lead this trial at Memorial Sloan Kettering, and Jarushka Naidoo, M.B.B.Ch., assistant professor of oncology, will lead at Johns Hopkins. For more information, click here.

New strategy for multiple myeloma immunotherapy

In recent decades monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both solid tumors and blood cancers. Monoclonal antibodies (mAb), as the name implies, are antibodies that are made by clonal cells derived from a single parent cells and therefore share the identical amino acid sequences.

One of the leading technologies to emerge in mAb-based treatment is CAR-T, where CAR stands for “chimeric antigen receptor”, and T represents T cells, a type of white blood cells that have pivotal roles in immune defenses. CARs are produced by combining together the gene for an antibody that recognizes a tumor antigen with the gene for a receptor that resides on the surface of the T cells; insert this new gene into a T cell and it will be precisely targeted at the tumor.

Theoretically, new antigens – molecules capable of inducing an immune response to produce an antibody – that arise from cancer-specific mutations of cell-surface proteins are excellent targets. However, mAb therapy targeting such antigens is impractical because of these proteins’ vast diversity within and between individual tumors, which renders identifying new cancer-specific target antigens difficult.

However, such challenges have driven researchers centered at Japan’s Osaka University to think outside of the box; cancer-specific antigen formed by the modification of proteins during or after synthesis, such as glycosylation (attachment of sugar moieties to protein) or conformational changes, might have been missed in previous analyses. The team believed new antigen epitopes, which is the part of an antigen recognized by the immune cells, could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.

“We applied this strategy to identify novel therapeutic targets for multiple myeloma (MM), a cancer that forms in a type of white blood cell called a plasma cell,” explains Naoki Hosen, lead author of the study, which was recently published in Nature Medicine. “Despite advances in MM treatment, relapse remains common. As such, there is an ongoing need for new therapeutic approaches, including mAb-based therapies.”

The team screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7, a cell-surface receptors that facilitate cell-extracellular matrix adhesion. MMG49 reacted to MM cells, but not other bone marrow cell types in MM patient samples. This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49. The resulting MMG49 CAR T was found to have anti-MM effects without damaging normal blood cells.

“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” study coauthor Yukiko Matsunaga says. “Therefore it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.”

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.

Palliative Care and Cancer Treatment

A cancer diagnosis is frightening and often impacts patients on both a physical and an emotional level. It can actually lead to symptoms such as pain, nausea, anxiety and depression. These symptoms, as well as those that are caused by the cancer and/or the cancer treatment, can be eased through the incorporation of palliative medicine into the patient’s care plan.

Palliative medicine, which is commonly referred to as palliative care, provides an extra layer of support to patients and their families throughout the cancer journey. This support can include both medical and holistic approaches to care depending on the patient’s wishes and personal circumstances.

“As a palliative care physician, I strive to get to know each patient individually by encouraging them to talk about their cancer journey and learning what is important to them. Many patients find this to be very helpful and therapeutic. By getting to know patients and finding ways to help them to manage their symptoms, I can help them live in a way in which their cancer diagnosis is not on their minds 24/7,” explains Ayelet Spitzer, D.O., Supportive Care Specialist, Valley-Mount Sinai Comprehensive Cancer Care.

Some examples of palliative care services are:

  • Symptom management
  • Support for complex decision managing
  • Goal setting
  • Advance care planning
  • Social and caregiver assessment and support
  • Spiritual care
  • Care coordination/transition management
  • Self-management techniques

“Please keep in mind that palliative care should not be confused with hospice care, which is palliative care provided during the end of life. All cancer patients can benefit from palliative care services, regardless of where they are on their cancer journey. In fact, most palliative care services are offered while patients are receiving cancer treatment. Palliative care is not about dying—it is about living life to the fullest,” adds Dr. Spitzer.