Study uncovers potential ‘silver bullet’ for preventing and treating colon cancer

In preclinical experiments, researchers at VCU Massey Cancer Center have uncovered a new way in which colon cancer develops, as well as a potential “silver bullet” for preventing and treating it. The findings may extend to ovarian, breast, lung, prostate and potentially other cancers that depend on the same mechanism for growth.

Led by Massey’s Deputy Director Steven Grossman, M.D., Ph.D., a team of scientists targeted the gene CtBP with a drug known as HIPP (2-hydroxy-imino phenylpyruvic acid) and were able to reduce the development of pre-cancerous polyps by half and return a normal lifespan to mice born with a predisposition to intestinal polyps. In humans, this condition is known as familial adenomatous polyposis, a devastating inherited disease that causes pre-cancerous polyps to grow in the intestine at a young age, often leading to the removal of portions of the colon to prevent cancer.

“This work opens up a whole new avenue for anti-cancer therapeutic development, as it shows that CtBP drives the actions of what are known as cancer stem cells, which are keys to cancer metastasis and resistance to chemotherapy,” says Grossman, who is also the Dianne Nunnally Hoppes Endowed Chair in Cancer Research and co-leader of the Developmental Therapeutics research program at Massey as well as professor and chair of the Division of Hematology, Oncology and Palliative Care in the Department of Internal Medicine at the VCU School of Medicine.

In contrast to other cancer-promoting genes, CtBP is not mutated in colon cancer; instead, it is overexpressed to the point where the cancer depends on it for growth. CtBP works to reprogram cells by repressing the expression of genes that typically prevent cancer through a form of cell suicide known as apoptosis while simultaneously promoting the expression of other genes that lead to cancer growth and metastasis.

The researchers found that CtBP can cause normal human cells to become cancerous when inserted into the cell’s DNA. In mouse models of familial adenomatous, treatment with HIPP significantly reduced intestinal polyps and increased survival while mice bred without the CtBP gene lived twice as long as those with it.

“In our experiments, HIPP acted almost as a chemical ‘silver bullet’ to prevent polyp formation, thereby reducing the risk of colon cancer,” says Grossman. “Also, we believe that anti-CtBP therapies such as HIPP may be able to complement current therapies to counter drug resistance and decrease metastasis, ultimately increasing our ability to control and cure colon cancer.”

This study is the latest in a line of research investigating CtBP by Grossman and his colleagues that began in 2010. Moving forward, they plan to continue testing derivatives of HIPP for the treatment of colon cancer and also see if their findings extend to breast, lung, ovarian and prostate cancers.

Risk-reducing mastectomy questioned for BRCA mutation carriers with prior ovarian cancer

Mutations in the BRCA gene correspond to a higher lifetime risk of developing breast and ovarian cancers, and many women who carry these mutations consider undergoing mastectomy or removal of the ovaries and fallopian tubes as preventive measures.

But for the subset of women with BRCA mutations who have already had ovarian cancer, risk-reducing mastectomy might not be worth the price tag. New research from the Duke Cancer Institute finds that for many women in this unique group, prophylactic mastectomy does not produce a substantial survival gain and is not cost-effective.

The finding is especially noteworthy because of updated National Comprehensive Cancer Network guidelines recommending that many women with ovarian cancer be considered for genetic testing regardless of family history. Now, more than ever before, some women with ovarian cancer are also learning that they carry a BRCA mutation.

“Risk-reducing mastectomy is costly and can require many months of follow-up and recovery,” said Charlotte Gamble, M.D., the study’s lead author and a resident physician at Duke University School of Medicine. “Our results emphasize that prophylactic mastectomy should be used selectively in women with both a BRCA mutation and a history of ovarian cancer.”

In the study, published online July 11 in the journal Annals of Surgical Oncology, Gamble and co-researchers constructed a statistical model comparing risk-reducing mastectomy to breast cancer screening, including mammogram and MRI. The model incorporated clinical factors such as the age at ovarian cancer diagnosis, time between ovarian cancer diagnosis and risk-reducing mastectomy, BRCA mutation status, cancer survival rates and treatment costs. Risk-reducing mastectomy was compared to breast cancer screening performed every six months following ovarian cancer diagnosis.

The study’s authors also considered a cost-effectiveness measurement called the incremental cost effectiveness ratio. Healthcare interventions where this ratio is less than $100,000 per year of life saved are commonly considered cost-effective in medical literature. The authors used the same threshold in this study.

According to the authors’ analysis, the benefit of risk-reducing mastectomy over screening alone largely depended on the patient’s age at the time of her ovarian cancer diagnosis and time to mastectomy:

For women diagnosed at any age with BRCA 1 and 2 gene mutations and within the first four years after ovarian cancer diagnosis, mastectomy was associated with a negligible gain in survival and was therefore not found to be cost-effective;

For women diagnosed at age 60 or older, regardless of time since ovarian cancer diagnosis, the gain in survival months was also negligible and the procedure was not cost-effective;

For women diagnosed at age 40 to 50 with BRCA 1 and 2 mutations and at least five years after an ovarian cancer diagnosis, the procedure was associated with a survival benefit of two to five months compared to screening and found to be cost-effective.

“Our study provides clarity on how a woman’s age and timing of a risk-reducing mastectomy after an ovarian cancer diagnosis impact the benefit of this procedure,” Gamble said. “Within the first five years, nobody benefited from risk-reducing mastectomy and after that threshold, survival gains were seen mostly in the youngest, healthiest ovarian cancer patients.”

“There is no right or wrong answer on how to manage breast cancer risk in this unique population,” added senior author Rachel Greenup, M.D., assistant professor of surgery at Duke. “However, we hope that our findings provide guidance to women and their doctors deciding if and when prophylactic mastectomy is beneficial following ovarian cancer treatment.”

Study shows biomarkers can predict which ER-positive breast cancer patients respond best to first-line therapy

Two challenges in treating patients with estrogen-positive breast cancer (ER+) have been an inability to predict who will respond to standard therapies and adverse events leading to therapy discontinuation. A study at The University of Texas MD Anderson Cancer Center revealed new information about how the biomarkers retinoblastoma protein (Rb) and cytoplasmic cyclin E could indicate which patients will respond best to current first-line therapies.

The study also discovered that combining the current therapy with autophagy inhibitors will result in using one-fifth of the dosage of the standard treatment, which could significantly reduce side effects associated with this therapy. Findings were published in the June 27 issue of Nature Communications.

Standard treatment, consisting of palbociclib, often has adverse side effects and not all ER+ patients respond to the therapy. Palbociclib inhibits proteins called CDK4 and CDK6 (CDK4/6) and tumor cells escape this inhibition by activating autophagy, a process allowing cancer cells to thrive even when starved of nutrients. By combining palbocicilb with autophagy inhibitors in cells that express normal Rb and nuclear cyclin E, the dose of palbociclib was significantly reduced.

Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, led a team that demonstrated how CDK4/6 and autophagy inhibitors synergistically induce cell senescence in Rb-positive cytoplasmic cyclin E-negative cancers. CDK4/6 inhibitors are approved by the Food and Drug Administration (FDA).

“Our findings could impact the majority of ER+ and HER2-negative breast cancers accounting for about 60 percent of advanced breast cancers,” said Keyomarsi. “We demonstrated for the first time evidence that Rb and cytoplasmic cyclin E status have a very strong effect on predicting response to the current standard first-line therapy for this population of patients, hormonal therapy plus palbociclib.We also discovered that by inhibiting the pathway such as autophagy that causes tumor cells to escape palbociclib growth inhibition, CDK4/6 inhibitor was more effective.”

Deregulation of cell cycle checkpoint proteins, such as CDK4/6, is a key hallmark of cancer, resulting in uncontrolled cellular growth and tumor formation. Some CDK4/6 inhibitors, including palbociclib, ribociclib and abemaciclib, have shown potential in pre-clinical and clinical studies in numerous solid tumors. Palbociclib has demonstrated benefits in Phase II and III trials in advanced ER+ breast cancers, doubling progression-free survival compared to drugs such as letrozole or fulvestrant, and is currently being evaluated clinically in other solid tumors.

“Data provided through The Cancer Genome Atlas revealed alterations in the CDK4/6/cyclin D pathway in about 35 percent of the patients, making them an ideal population for targeting CDK4/6,” said Keyomarsi. “Our study revealed that inhibition of CDK4/6 and autophagy pathways cooperate to induce sustained growth inhibition and senescence in vitro and in vivo, in breast and other solid tumors and showed how autophagy inhibition can significantly decrease the dose of palbociclib required to treat breast cancer patients. We believe this new strategy can improve the efficacy of other CDK4/6 inhibitor treatments like ribociclib and abemaciclib.”

The team’s findings indicated how Rb and cyclin E status predicts response to a combination of CDK4/6 and autophagy inhibition in pre-clinical models and that autophagy blockade is successful in reversing resistance to palbociclib.

“Palbociclib resistance is a significant limitation of this treatment which is not curative and does not prolong survival even though transient responses and prolongation of response have formed the basis of FDA approval,” said Keyomarsi. “Our study provides evidence that models of hormone receptor-negative cancer and even non-breast cancer malignancies can respond to the combination of palbociclib and autophagy inhibition, when selected based on Rb and cyclin E isoform status, representing a completely new therapeutic opportunity for these cancers.”

Keyomarsi and colleagues anticipate future clinical studies based on this pre-clinical and clinical evidence with the aim of developing translational and clinical applications.

New cellular imaging paves way for cancer treatment

Researchers at the Universities of York and Leiden have pioneered a technique which uses florescent imaging to track the actions of key enzymes in cancer, genetic disorders and kidney disease.

Scientists hope this new development will aid drug design for new anti-cancer, inflammation and kidney disease treatments.

It will also provide diagnostic tools for disease identification and allow medical professionals to measure the effectiveness of drug treatment regimes in an easy laboratory manner.

Studying heparanase – a key enzyme in the development and metastasis of human cancers – scientists unveiled new fluorescent imaging agents that detect enzyme activity in healthy and diseased tissues.

The research, published this week in Nature Chemical Biology, builds upon previous work revealing heparanase’s three-dimensional structure.

Heparanase is a long-studied protein in human tissues involved in breaking down the complex sugars of the “extracellular matrix” – the material surrounding cells that provides structure and stability.

Heparanase dysfunction is linked to the spread of cancers both through the breakdown of this matrix and via the subsequent release of “growth factors” – chemicals that promote tumour development.

Through its remodelling of the matrix, heparanase is also a key player in inflammation and kidney disease. It is therefore a major drug, and diagnostic probe, target.

Gideon Davies, Professor of Structural Enzymology and Carbohydrate Chemistry at the University of York, said: “Heparanase is a key human enzyme. Its dysregulation is involved in inherited genetic disorders, and it is also a major anti-cancer target and increasingly implicated in kidney disease.

“Our work allows us to probe the activity of heparanase in human samples – allowing early disease identification and a direct measure of the success of drugs in humans.

“This work is a great example of the power of EU collaboration and science funding from the European Research Council.”

Hermen Overkleeft, Professor of Bio-Organic Synthesis at Leiden University, added: “This work reveals the power of activity-based protein profiling: the probe described here at once enables screening for heparanase inhibitors from large compound collections and is a lead compound for drug development in its own right.

“While the road to heparanase-targeting clinical drugs is long and fraught with risks, with this work we believe to have taken a major step in realizing the therapeutic potential of this promising clinical target.”

Thorough Genotyping and Repurposed Drugs Key to Treating Small-Cell Lung Cancer, says Cancer Expert

Small cell lung cancer (SCLC) is an aggressive disease characterized by quick growth and spread. While there has been a gradual decrease in incidence of SCLC in recent years, likely reflecting the decreased prevalence of tobacco use, little progress has been made in treating SCLC due to its complex pathogenesis.

The majority of patients, including those with limited-stage disease and those who initially respond to chemo- and radiation- therapy (two traditional pillars of cancer therapy), become resistant to treatment resulting in a very small percentage (approximately 6%) who survive 5 years after being diagnosed.

Smoking is the main risk factor for SCLC, with only 2-3% of patients categorized as never-smokers.

Identifying Therapeutic Targets in Small-Cell Lung Cancer

From the molecular point of view, SCLC is characterized by a multitude of alterations, owing to the fact that cells are exposed to a myriad of carcinogens contained in cigarette smoke, which bind and mutate DNA. These alterations affect numerous genes and pathways, but among these there are few obvious therapeutic targets. This means that the driver genes responsible for most SCLC development and progression have yet to be identified with any certainty.

However, new high-throughput technologies, which allow comprehensive gene profiling, have revealed promising findings. For example, 20% of SCLC patient tumors bear alterations in the MYC gene family. This discovery has helped to identify a subset of patients sensitive to an oncogenic kinase downstream in the MYC pathway, allowing for better designed, biomarker-driven clinical trials for these, often repurposed, therapeutic agents.

Similarly, PARP1 and Notch have been found overexpressed in SCLC. In order to target PARP1, an enzyme which, when it malfunctions, leads to replication of damaged DNA, researchers are currently evaluating the efficacy of PARP inhibitors for treatment of SCLC. And, to investigate targeting of the Notch signaling pathway, which influences the cellular life-cycle, the FDA is in the process of approving Tarextumab, a selective Notch inhibitor, in the treatment of SCLC.

Another issue with SCLC tumors is that they are mostly characterized by the loss of two crucial oncosuppressor genes, named RB, RB2\p130 i and TP53, which are less actionable pharmaceutically because it is much more difficult to restore a loss of function rather than block an oncogenic gain of function. Although challenging, researchers are nonetheless trying to develop strategies in this direction.

Repurposing Existing Drugs

Also important to the progress of SCLC therapies, more effective drug identification and testing, through the use of powerful mouse models of the human disease, put researchers in a good position to tackle this cancer type and attempt better defined targeted approaches.

Recent immunotherapy approaches have emerged as a significant new pillar in cancer therapy and are being assessed in numerous clinical trials for a multitude of tumors, including SCLC. In particular, two new agents, nivolumab and ipilimumab, have recently been developed to treat other forms of cancer, such as unresectable or metastatic malignant melanoma, advanced non-small-cell lung cancer (NSCLC), and advanced renal-cell carcinoma. These agents have also been tested for applications in SCLC. Nivolumab and ipilimumab are constituted by monoclonal antibodies functioning through direct inhibition of CTLA4 and PD1, respectively, which are key negative regulators of the antitumoral immune function. Bristol-Myers Squibb (BMS) was able to obtain the National Comprehensive Cancer Network indication for use of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The indication was achieved upon the publication on Lancet Oncology by Scott Antonia and colleagues, who reported the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab, achieving antitumour activity with durable responses and manageable safety profiles in previously treated SCLC patients, enrolled in the CheckMate-032 clinical trial.

Data was also presented at the World Lung Cancer Congress on the immunotherapy drug pembrolizumab, another therapeutic antibody against PD1, already approved for other diseases, which showed good efficacy.

One additional drug in this category is rovalptizumab teserine, a first-in-class antibody-drug conjugate comprised of a humanized monoclonal antibody against DLL3 and a toxin. DLL3 is a Notch ligand found to be expressed on 80% of SCLC. There is a 3rd line trial which is biomarker driven, meaning that they test for DLL3 expression and patients are eligible if they have “high” DLL3.

 

First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

Virginia Tech Researchers Help the Body Protect Itself Against Inflammation and Colon Cancer

Could inflammatory bowel disease and colon cancer be prevented by changing the shape of a single protein?

There is an intimate link between uncontrolled inflammation in the gut associated with inflammatory bowel disease and the eventual development of colon cancer. This uncontrolled inflammation is associated with changes in bacteria populations in the gut, which can invade the mucosal tissue after damage to the protective cellular barrier lining the tissue.

But Virginia Tech researchers found that modifying the shape of IRAK-M, a protein that controls inflammation, can significantly reduce the clinical progression of both diseases in pre-clinical animal models.

The altered protein causes the immune system to become supercharged, clearing out the bacteria before they can do any damage. The team’s findings were published in eBioMedicine.

“When we tested mice with the altered IRAK-M protein, they had less inflammation overall, and remarkably less cancer,” said Coy Allen, an assistant professor of inflammatory disease in the Department of Biomedical Sciences and Pathobiology in the Virginia-Maryland College of Veterinary Medicine and a Fralin Life Science Institute affiliate.

The next step, he said, will be to evaluate these findings in human patients through ongoing collaborations with Carilion Clinic and Duke University. The team is also evaluating their findings in laboratory-assembled ‘mini-guts’—live tissue models that Allen and his team assembled by growing intestinal stem cells on petri dishes to form highly complex small intestinal and colon tissue.

“Ultimately, if we can design therapeutics to target IRAK-M, we think it could be a viable strategy for preventing inflammatory bowel disease and cancer,” said Allen.

Colon cancer is the second leading cause of cancer-related deaths in the United States and the third most common cancer in men and women, according to the Centers for Disease Control and Prevention.

More than ten Virginia Tech faculty members and students are working on the project, including co-principal investigator Liwu Li, a professor of biological sciences in the College of Science; Clay Caswell, an assistant professor of bacteriology in the veterinary college; Rich Helm, an associate professor of biochemistry in the College of Agriculture and Life Sciences; Dan Slade, an assistant professor of biochemistry in the College of Agriculture and Life Sciences; and Tanya LeRoith, a clinical associate professor of anatomic pathology in the veterinary college.

Study Tightens Connection Between Intestinal Microorganisms, Diet, and Colorectal Cancer

A new study provides some of the strongest evidence to date that microorganisms living in the large intestine can serve as a link between diet and certain types of colorectal cancer, the lead authors at Dana-Farber Cancer Institute and Massachusetts General Hospital report.

The paper, published online today by JAMA Oncology, focuses on Fusobacterium nucleatum, one of hundreds of types of bacteria that dwell in humans’ large intestines, and one that is thought to play a role in colorectal cancer. By tracking the diets of more than 137,000 people for decades and examining more than 1,000 colorectal tumor samples for F. nucleatum, the researchers determined that individuals with a “prudent” diet – rich in whole grains and fiber – had a lower risk of developing colorectal cancer containing the bacterium, but their risk for colorectal cancer that lacked the bacterium was essentially unchanged.

Prudent diets appear to protect against colorectal cancer. The new study suggests that healthy foods may achieve these benefits, in part, by altering the relative amounts of various microorganisms in the digestive tract, including F. nucleatum.

“Though our research dealt with only one type of bacteria, it points to a much broader phenomenon – that intestinal bacteria can act in concert with diet to reduce or increase the risk of certain types of colorectal cancer,” said Shuji Ogino, MD, PhD, of Dana-Farber, Harvard T.H. Chan School of Public Health, and Brigham and Women’s Hospital, the co-senior author of the study with Charles Fuchs, MD, MPH, director of the Gastrointestinal Cancer Center at Dana-Farber and Brigham and Women’s, and Andrew Chan, MD, MPH, of Massachusetts General Hospital, Brigham and Women’s, and the Broad Institute of MIT and Harvard.

“These data are among the first in humans that show a connection between long-term dietary intake and the bacteria in tumor tissue. This supports earlier studies that show some gut bacteria can directly cause the development of cancers in animals,” added Chan.

The research drew on dietary records of 137,217 participants in the Nurses’ Health Study and Health Professionals Follow-up Study – large-scale health-tracking studies – some of whom developed colon or rectal cancer over a period of decades. The researchers measured the levels of F. nucleatum in the patients’ tumor tissue and blended these data with information of diet and cancer incidence.

“Recent experiments have suggested that F. nucleatum may contribute to the development of colorectal cancer by interfering with the immune system and activating growth pathways in colon cells,” Ogino remarked. “One study showed that F. nucleatum in the stool increased markedly after participants switched from a prudent to a Western-style, low fiber diet. We theorized that the link between a prudent diet and reduced colorectal cancer risk would be more evident for tumors enriched with F. nucleatum than for those without it.”

That is precisely what the study results showed: Participants who followed a prudent diet had a sharply lower risk of developing colorectal cancer laden with F. nucleatum. But they received no extra protection against colorectal cancers that didn’t contain the bacteria.

“Our findings offer compelling evidence of the ability of diet to influence the risk of developing certain types of colorectal cancer by affecting the bacteria within the digestive tract,” Ogino commented.

“The results of this study underscore the need for additional studies that explore the complex interrelationship between what someone eats, the microorganisms in their gut, and the development of cancer,” said Chan.

Tulane Researchers Find Tumor-Suppressing Protein Actually Promotes Cancer

Tulane University researchers have discovered that the protein PHLDB3, thought to be a potential tumor suppressor, actually allows cancer cells to thrive in pancreatic, prostate, colon, breast, lung, and other common cancers. The discovery could explain how cancer is able to overcome p53 – a key tumor-suppressing protein.

The findings, recently published in Nature Communications, could eventually lead to targeted diagnostic tests and treatments of certain types of cancer.

“Now that we’ve identified the molecule, we could utilize it as an anti-cancer target,” said lead study author Dr. Hua Lu, the Reynolds and Ryan Families Chair in Translation Cancer at Tulane. “This target can be used to develop a drug that would hopefully, combined with chemotherapy, be more effective and less toxic.”

Scientists have long known that protein p53 protects against cancer by triggering cells with DNA damage to self-destruct before they become malignant. P53 is kept in check by two genes, MDM2 and MDMX, which regulate its growth and demise. While overproduction of either the genes or the protein is harmful, a balanced production of both p53 and the genes allows for normal cell development.

Lu and his team discovered that PHLDB3 works with MDM2 to inhibit p53, promoting tumor growth. The protein could also cause therapeutic resistance for some late state cancers.

To ensure that PHLDB3 is an optimal drug target, Lu says the next step is to further validate the cancer-causing role of PHLDB3 by using mouse model systems either dependently or independently of p53. He says it’s also important to understand the protein’s biological role in cellular signaling and normal animal development as well as to consolidate its role in human cancer development, progression and drug-resistance.

Researchers Find Key Genetic Driver for Rare Type of Triple-Negative Breast Cancer

Researchers find key genetic driver for rare type of triple-negative breast cancer

New mouse model leads to surprising discovery that sheds light on metaplastic breast cancer

For more than a decade, Celina Kleer, M.D., has been studying how a poorly understood protein called CCN6 affects breast cancer. To learn more about its role in breast cancer development, Kleer’s lab designed a special mouse model – which led to something unexpected.

They deleted CCN6 from the mammary gland in the mice. This type of model allows researchers to study effects specific to the loss of the protein. As Kleer and her team checked in at different ages, they found delayed development and mammary glands that did not develop properly.

“After a year, the mice started to form mammary gland tumors. These tumors looked identical to human metaplastic breast cancer, with the same characteristics. That was very exciting,” says Kleer, Harold A. Oberman Collegiate Professor of Pathology and director of the Breast Pathology Program at the University of Michigan Comprehensive Cancer Center.

Metaplastic breast cancer is a very rare and aggressive subtype of triple-negative breast cancer – a type considered rare and aggressive of its own. Up to 20 percent of all breast cancers are triple-negative. Only 1 percent are metaplastic.

“Metaplastic breast cancers are challenging to diagnose and treat. In part, the difficulties stem from the lack of mouse models to study this disease,” Kleer says.

So not only did Kleer gain a better understanding of CCN6, but her lab’s findings open the door to a better understanding of this very challenging subtype of breast cancer. The study is published in Oncogene.

“Our hypothesis, based on years of experiments in our lab, was that knocking out this gene would induce breast cancer. But we didn’t know if knocking out CCN6 would be enough to unleash tumors, and if so, when, or what kind,” Kleer says. “Now we have a new mouse model, and a new way of studying metaplastic carcinomas, for which there’s no other model.”

One of the hallmarks of metaplastic breast cancer is that the cells are more mesenchymal, a cell state that enables them to move and invade. Likewise, researchers saw this in their mouse model: knocking down CCN6 induced the process known as the epithelial to mesenchymal transition.

“This process is hard to see in tumors under a microscope. It’s exciting that we see this in the mouse model as well as in patient samples and cell lines,” Kleer says.

The researchers looked at the tumors developed by mice in their new model and identified several potential genes to target with therapeutics. Some of the options, such as p38, already have antibodies or inhibitors against them.

The team’s next steps will be to test these potential therapeutics in the lab, in combination with existing chemotherapies. They will also use the mouse model to gain a better understanding of metaplastic breast cancer and discover new genes that play a role it its development.

“Understanding the disease may lead us to better ways to attack it,” Kleer says. “For patients with metaplastic breast cancer, it doesn’t matter that it’s rare. They want – and they deserve – better treatments.”

Breast and Cervical Cancer Screening Rates Are Low in Women with Advanced Kidney Disease

new study indicates that many women with advanced kidney disease are not receiving recommended breast or cervical cancer screening, even though they face a higher risk of developing cancer than women in the general population. The findings appear in an upcoming issue of the Clinical Journal of the American Society of Nephrology (CJASN).

Cancer is a significant cause of illness and death in patients with chronic kidney disease (CKD), with an approximately twofold higher prevalence than the general population. The increased risk appears to be specific for urinary tract, viral-related, digestive, and breast
cancers. Therefore, breast and cervical cancer screening is especially important in women with CKD.

A team led by Germaine Wong, PhD, (The University of Sydney, in Australia), Jade Hayward, and Danielle Nash, PhD (Institute for Clinical Evaluative Sciences, ICES Western facility, in Ontario, Canada) examined patterns of breast and cervical cancer screening in women based on CKD stage and age. The retrospective study included information from 2002 to 2013 from the Ontario, Canada administrative healthcare databases. For their analyses on breast cancer screening and cervical cancer screening, the investigators included 141,326 and 324,548 women, respectively.

Older women with co-morbidities and with advanced stage kidney disease requiring dialysis were less likely to undergo routine breast and cervical cancer screening compared with younger women with early stage CKD. The two-year cumulative incidences of breast cancer screening were 61% among women without CKD, 54% for those with CKD stage 3, 37% for CKD stages 4 and 5, and 26% for women with kidney failure who were on dialysis. Similar patterns were observed for the three-year cumulative incidences of cervical cancer screening. Older age, greater comorbidities, and lower income were associated with a lower rate of screening.

“These results reflect the inherent healthcare priorities of dialysis patients: older women on dialysis may not have the capacity to deal with the complexity of dialysis management and may have potentially neglected less imminent issues such as preventive healthcare and early cancer detection,” said Dr. Wong. “Given that cancer screening has the potential to improve cancer outcomes, targeted strategies to inform shared decision making in screening is critical.”

In an accompanying editorial, Deidra Crews, MD, ScM and Waseem Khaliq, MBBS, MPH, (Johns Hopkins University School of Medicine) noted that “enhanced coordination of care between nephrologists, general practitioners and women’s health care providers may serve to promote cancer screening among women with CKD. Ultimately, however, nephrologists may forge long-term trusting relationships with kidney patients that will afford them the greatest opportunity to engage in shared-decision making together and select the cancer screening plan that is most appropriate for the patient’s individual health status and personal priorities.”

Penn Experts Call for Expansion of Molecular Imaging in Precision Cancer Care

New molecular imaging technologies can make it easier to diagnose, monitor, and treat cancers while potentially saving patients from undergoing therapies that are likely to be ineffective and playing a role in minimizing side effects, according to experts from the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania. In a review published online today in JAMA Oncology, the Penn team says finding a way to use these techniques more widely in clinical settings should be a top priority.

Precision cancer care focuses on identifying the specific biomarkers of a patient’s cancer, which can help doctors make decisions about the best treatment options. A traditional way to learn about the genetic makeup of cancer is through a biopsy – in which doctors have to physically remove tissue from a patient and then examine it. But new molecular imaging, which can be used to complement the biopsy and is noninvasive, can provide added benefit in certain cases, especially when multiple examinations are needed.

There are four main areas where molecular imaging can have a major impact, according to the study’s lead author David A. Mankoff, MD, PhD, the Gerd Muehllehner Professor of Radiology and director of the PET Center at the Perelman School of Medicine at the University of Pennsylvania. First, it can help identify patients most likely to benefit from targeted therapy.

“Once we start treatment, it can also help us plan radiotherapy treatment and help define the boundaries of the active tumor,” Mankoff said.

Second, it can monitor the movement of drugs throughout the body to guide drug dosing and minimize side effects. Similarly, it can also monitor whether those drugs are having an effect. Finally, all of this data can be combined to predict patient outcomes including overall survival.

Unlike X-ray and ordinary magnetic resonance imaging (MRI), which reveal the large-scale structures of tissues in the body, molecular imaging uses special imaging “probe” compounds—injected into the patient—to highlight a desired molecular target in a tissue of interest. FDG-PET, one of the only molecular imaging techniques routinely used in oncology, employs a glucose-like probe, FDG, with a radioactive isotope of fluorine attached as a beacon. Once it is injected into the bloodstream, the FDG probe quickly accumulates in tumors, which tend to make heavy use of glucose. Thus, it “lights up” those tumors on a PET (positron emission tomography) scan.

FDG-PET, a method that the University of Pennsylvania helped pioneer, has been used for more than two decades to detect tumors and determine the extent to which cancer has spread. But the newer PET probes now in development and testing are meant for many other applications in cancer medicine.

Two new classes of probe that show particular promise are designed to bind to estrogen and HER2 receptors. Breast, uterine, and ovarian tumors often use these receptors to boost their growth, and many cancer drugs target them. Detecting the presence of tumor estrogen or HER2 receptors with PET scans would enable oncologists to examine all sites of cancer for each patient, choose the appropriate drug treatment more quickly, monitor the tumor for changes that would necessitate a switch to another treatment, and even evaluate how well a drug is hitting its receptor targets.

Imaging with the new PET probes also could reveal receptors or other tumor-related markers at sites where the cancer may have spread, including bone, which is much harder to biopsy.

The probes targeted to breast cancer have shown great promise so far in breast cancer clinical trials, and Mankoff and his Penn Medicine colleagues have helped lead this research effort. One national, multi-center trial focused on the estrogen receptor is co-chaired by oncologist Amy Clark, MD, MSCE, a co-author of the review and an assistant professor of medicine at the Abramson Cancer Center at the University of Pennsylvania. Another smaller trial of estrogen receptor imaging is underway at the Abramson Cancer Center’s 2-PREVENT Translational Center of Excellence.

“Many of these methods are already being studied in clinical trials, but the path from clinical trials to routine clinical use is seldom easy,” Mankoff said. “And molecular imaging methods face some particularly challenging hurdles such as the need to deliver the short-lived imaging probes to centers performing the imaging.”

Because these methods are so new to oncologists, there is no standard procedure for testing them, or for making an empirical case for their clinical value to the FDA, medical insurers, and ultimately oncologists themselves.

“We don’t have a good framework yet for moving these potentially powerful diagnostic tools into routine clinical use,” Mankoff said. “Among other things, we need to bring the imaging and oncology communities together to find the best way forward.”

Mankoff and his colleagues argue that making a strong clinical case for these new imaging techniques will mean demonstrating their ability to improve traditional treatment outcomes such as progression-free survival and quality of life. Clinical trials of these methods also could take into account the value of avoiding ineffective treatments. In one recent trial, researchers showed that a combination of FDG and HER2-targeted PET imaging was 100 percent accurate in predicting patient responses to a costly new anti-HER2 breast cancer drug.

“In that case, molecular imaging could have directed treatment to patients highly likely to benefit and spared many other patients the toxic effects and costs of ineffective therapy,” Mankoff said.

Above all, Mankoff says testing of new imaging methods should focus on applications where they clearly represent an advance for patients over other imaging or biopsy-based techniques.

“These clinical trial results for the new molecular imaging methods are going to be compelling for patients and their referring oncologists only when they address clinical challenges not met by existing approaches,” he said.

Reducing Radiation Successfully Treats HPV-Positive Oropharynx Cancers and Minimizes Side Effects

Human papillomavirus-positive oropharynx cancers (cancers of the tonsils and back of the throat) are on rise. After radiation treatment, patients often experience severe, lifelong swallowing, eating, and nutritional issues. However, new clinical trial research shows reducing radiation for some patients with HPV-associated oropharyngeal squamous cell carcinomas can maintain high cure rates while sparing some of these late toxicities.

“We found there are some patients have very high cure rates with reduced doses of radiation,” said Barbara Burtness, MD, Professor of Medicine (Medical Oncology), Yale Cancer Center, Disease Research Team Leader for the Head and Neck Cancers Program at Smilow Cancer Hospital, and the chair of the ECOG-ACRIN head and neck committee. “Radiation dose reduction resulted in significantly improved swallowing and nutritional status,” she said.

The study, published in the December 26 issue of the Journal of Clinical Oncology, showed that patients treated with reduced radiation had less difficulty swallowing solids (40 percent versus 89 percent of patients treated with standard doses of radiation) or impaired nutrition (10 percent versus 44 percent of patients treated with regular doses of radiation).

“Today, many younger patients are presenting with HPV-associated squamous cell carcinoma of the oropharynx,” said Dr. Burtness. “And while traditional chemoradiation has demonstrated good tumor control and survival rates for patients, too often they encounter unpleasant outcomes that can include difficulty swallowing solid foods, impaired nutrition, aspiration and feeding tube dependence,” said Dr. Burtness. “Younger patients may have to deal with these side effects for decades after cancer treatment. We want to help improve our patients’ quality of life.”

The study included 80 patients from 16 ECOG-ACRIN Cancer Research Group sites who had stage three or four HPV-positive squamous cell carcinoma of the oropharynx, and were candidates for surgery. Eligible patients received three courses of induction chemotherapy with the drugs cisplatin, paclitaxel, and cetuximab. Patients with good clinical response then received reduced radiation.

Study results also showed that patients who had a history of smoking less than 10 packs of cigarettes a year had a very high disease control compared with heavy smokers.

University Of Minnesota Researchers Win Breast Cancer Challenge Award

The University of Minnesota announced today that it is one of two grand prize winners in the National Cancer Institute’s Up for A Challenge (U4C) Breast Cancer Challenge Award offered in partnership with Sage Bionetworks. The recognition will help further the University’s innovative work in exploring genetic connections in breast cancer research.

Researchers from the University of Minnesota’s College of Science and Engineering and Masonic Cancer Center are using a unique computational methodology to examine how combinations of genetic variants are tied to a person’s chances of getting breast cancer. They used data from published genome-wide association studies (GWAS) to help identify novel molecular pathways involved in breast cancer susceptibility.

“We’ve applied this innovative methodology to other diseases, like Parkinson’s and heart disease, but this award will jump start our efforts within the breast cancer research community,” said Chad Myers, an associate professor of computer science and engineering.

In addition to Myers, the interdisciplinary research team for the U4C challenge includes Wen Wang, a University of Minnesota Ph.D. student in computer science and engineering; Carol Lange, a professor of medicine in the Masonic Cancer Center, University of Minnesota; and Zhiyuan (Zach) Xu, a University of Minnesota graduate student.

The Minnesota group’s work builds upon Myers’ previous research that looks at genes as a social network of the body, interacting in groups, rather than as loners. Work on developing a landmark genetic interaction map of yeast cells with 6,000 genes provides new insight on mapping human cells with 20,000 genes. By understanding how thousands of genes coordinate with one another to orchestrate cellular life, we can begin to understand, and thwart, the culprits behind diseases, with a potential for developing finely-tuned therapies.

The method they applied to the breast cancer competition was developed over the last several years as part of a collaboration with Professor Vipin Kumar’s lab in the University of Minnesota’s Department of Computer Science and Engineering.

Breast cancer is the second most common cause of cancer death in women in the United States. An estimated 246,660 new cases of invasive breast cancer are expected to be diagnosed among women (2,660 in men) in the United States in 2016, with an estimated 40,450 deaths.

Genome-wide association studies (GWAS) have helped to identify more than 90 common genetic variations that are associated with breast cancer risk. The goal of the U4C challenge is to use innovative approaches to identify novel pathways—including new genes or combinations of genes, genetic variants, or sets of genomic features—involved in breast cancer susceptibility in order to generate new biological hypotheses about how to understand and better treat the disease.

In addition to a $20,000 award, the U4C Breast Cancer Challenge Award winners are being invited to submit papers highlighting their results to a special issue of the academic journal PLoS Genetics that will be published later this year.

Protein Network Linked To Cancer Is Critical To Male Fertility

Researchers studying reproductive science identified a network of proteins often linked to cancer as also important to male fertility and the birth of healthy offspring, according to a study in the Oct. 18 online issue of Cell Reports.

The study by Satoshi Namewaka, PhD, and colleagues at Cincinnati Children’s Hospital Medical Center focuses on the precise epigenetic regulation of the sex chromosomes, which is important to germline cells that make male sperm.

Epigenetics involves changes in organisms caused by modifications to gene expression, rather than alterations in the genetic code. Scientists increasingly study the epigenetics of reproduction to learn how environmental exposures or lifestyle may affect fertility or inherited traits in offspring.

The current study looks at the Fanconi anemia (FA) pathway, a network of 21 proteins that normally work to repair DNA damage in the body’s cells. Mutations in the FA pathway can lead to severe anemia, genetic instability and different cancers. But the current study also uncovers roles in ensuring healthy human reproduction.

“Our data show the FA pathway regulates epigenetic programming in the germline and has an impact on reproduction,” says Namewaka, lead author in the Division of Reproductive Sciences at Cincinnati Children’s. “Understanding the exact role of FA proteins in this regulation may also be important for understanding the substantial fertility defects associated with FA and the role of FA proteins in DNA repair.”

The study is part of a much larger body of reproductive science exploring the causes of infertility, premature birth, birth defects and miscarriage – all still major health problems in the world.

Namekawa’s team reports that during meiosis – a critical biological stage for the production of genetically healthy sperm – FA proteins accumulate on the male sex chromosomes. Certain FA proteins work with an enzyme called RNF8 to regulate histones, which form the spool that DNA wraps around inside a cell’s nucleus.

The researchers tested the FA-DDR (DNA damage response) network’s regulation of this process by studying meiosis in eight different mouse models. The mice were deficient for DDR proteins, including several Fanconi anemia proteins. This allowed the research team to unravel how FA-DDR proteins function in a pathway to regulate the male sex chromosomes, a key finding in reproductive science since disrupted sex chromosome regulation results in male infertility.

Data indicate that genetically modified mice lacking FA-DDR proteins are infertile and have substantial defects in the regulation of the male sex chromosomes during meiosis.

Scientists continue their research by digging deeper into how and when FA proteins and other DNA damage response proteins interact during meiosis, and how this affects sperm production and fertility in laboratory mouse models.

Brain Cancer And Leukemia: New Molecular Mechanisms Decoded

Brain cancer and leukemia are two potentially fatal diseases that affect thousands of Canadians each year. But a joint study conducted by researchers Frederick Antoine Mallette, of the Maisonneuve-Rosemont Hospital Research Centre and the University of Montreal, and Marc-Étienne Huot, of Laval University, and published in the prestigious scientific journal Nature Communications has uncovered new molecular causes of brain cancer and leukemia.

We already knew the existence of a mutation phenomenon involving certain metabolic enzymes called isocitrate dehydrogenases 1 and 2 (IDH1/2) in various forms of brain cancer, including gliomas and glioblastomas, and in acute myeloid leukemia. Although the mutated forms of IDH1/2 appear to contribute to cancer formation, until now we had only limited understanding of the ways in which these metabolic defects caused cancer. Research conducted by Mélissa Carbonneau, a master’s student in Professor Mallette’s laboratory, has helped to better understand the effect of IDH1/2 mutations in cancer by demonstrating their role in activating the pathways involved in cell proliferation and survival.

“With the identification of the molecular modes of action that contribute to cancer in patients carrying IDH1/2 mutations, it is now possible to consider personalized treatment to potentially improve therapeutic response,” said Dr. Mallette.
Some statistics

It is estimated that in 2015, 3,000 Canadians were diagnosed with brain and spinal cord cancer, and 6,200 Canadians were diagnosed with leukemia.

New Model For Understanding Myeloma

All cancers originate from an earlier, or precursor, state — such as a benign or asymptomatic condition. To develop new approaches to cancer prevention, scientists have attempted to grow tumor cells from precursor states in animal models. Myeloma — a type of cancer that forms in white blood cells — is an example of a cancer that is preceded by a condition called monoclonal gammopathy.

In a new study, Yale professors Madhav Dhodapkar, Richard Flavell, and their co-authors describe new mouse models, wherein mice carry human versions of six genes that are essential for growth of tumor cells. The found that when the humanized mice were injected with tumor and non-tumor cells, both cell types were able to grow. The finding provides a potential new approach to understanding how myeloma develops and how to prevent it.

Yale Researchers Find Genes Behind Aggressive Ovarian And Endometrial Cancers

In a major breakthrough for ovarian and uterine cancers, Yale researchers have defined the genetic landscape of rare, highly aggressive tumors called carcinosarcomas (CSs), pointing the way to possible new treatments.

The findings are published in the Oct. 10 online early edition of Proceedings of the National Academy of Sciences.

Endometrial and ovarian cancers are the most prevalent gynecologic tumors in women, with over 76,160 newly diagnosed cases and about 14,270 deaths in 2015 in the United States alone. Although CSs comprise only 2%-5% of all uterine malignancies and 1%-2% of all ovarian tumors, they are responsible for a disproportionate number of deaths due to their high biologic aggressiveness and resistance to standard treatments, such as radiation and chemotherapy.

The collaborative research team — which included experts in gynecological cancer, genomics, pathology and computational biology— performed a comprehensive genetic analysis of ovarian and endometrial CSs. The team collected tumors from 68 women affected with ovarian and uterine CSs to try to determine the molecular basis of the tumor’s aggressive behavior. They sequenced all the genes from the tumors and identified mutations that are crucial for these tumors to grow. The team also studied the copy number variations — genes that are not mutated but are amplified in the tumors to give them a growth advantage over normal tissues.

“We identified a number of new genes that are frequently mutated in CS,” said senior author Alessandro Santin, M.D., professor of obstetrics, gynecology and reproductive sciences at Yale School of Medicine, and program leader of the gynecological cancers research program at Smilow Cancer Hospital at Yale-New Haven and a member of Yale Cancer Center.

“In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas, we found an excess of mutations in genes encoding specific groups of proteins, which may potentially explain their mixed tissue characteristics,” said Santin.

“We’ve established unequivocally the common genetic origin of these tumors as epithelial tumors,” he added. “Importantly, by studying the genetics of both the carcinomatous and sarcomatous elements of these tumors, we demonstrated that the transition from carcinoma to sarcoma, which represents one of the main characteristics of these tumors, may happen at different times during the evolution of these cancers.”

Reactome Announces Annotation And Release Of 10,000th Human Protein

The European Bioinformatics Institute (EMBL-EBI), the New York University School of Medicine and the Ontario Institute for Cancer Research (OICR) today announced a major milestone in the Reactome project: the annotation and release of its 10,000th human protein, making it the most comprehensive open access pathway knowledgebase available to the scientific community.

Reactome (www.reactome.org) relates human genes, proteins and other biomolecules to the biological pathways and processes in which they participate. It is a key resource for the biomedical research community, and is widely used by scientists around the world to interpret high-throughput experiments in genetics, genomics and proteomics.

The human genome contains roughly 20,000 protein-coding genes in total, so the annotation of the 10,000th protein means that Reactome now covers half of the protein-coding portion of the genome.

“We are pleased to reach this milestone and to share the results with the research community,” said Dr. Lincoln Stein, Interim Scientific Director of OICR, Director of OICR’s Informatics and Bio-computing Program and a Principal Investigator on the Reactome project. “Today’s release, which is the result of over a decade of hard work and collaboration, will help researchers in their effort to better understand how genomic variation leads to diseases like cancer, to develop methods to detect those diseases at an earlier stage and to treat patients more effectively.”

Henning Hermjakob at EMBL–EBI and Peter D’Eustachio at the New York University School of Medicine are also Principal Investigators on the project.

By relating genes and proteins to normal and abnormal biological pathways, Reactome provides sophisticated tools for identifying patterns in large datasets. For example, researchers can explore an experiment in Reactome that identifies thousands of genes involved in a disease, and reduce the data to a more targeted set of pathways for further study. By combining the resulting dataset with other resources, they are well placed to identify drugs and protein targets that might reverse undesirable pathway alterations, or discover ways to diagnose the disease at an early stage.

Via its website, online tools, and specialized visualization and analysis applications, Reactome has been incorporated into more than 400 third-party genome analysis tools, and has been cited more than 4,000 times in the scientific literature.

“Congratulations to the Reactome team on this major milestone,” said Reza Moridi, Minister of Research, Innovation and Science. “Through international collaborations such as this, Ontario researchers are making great strides in fighting disease on a global scale and I look forward to witnessing ongoing success with transformative discoveries that impact the lives of Ontarians every day.”

Yale Study Identifies New Way To Suppress Lung Tumors

Lung cancer cell growth depends on certain proteins that require the addition of sugar molecule chains to become active. Scientists have long thought that the addition of these sugar chains is like an on or off switch, and that blocking their addition would be harmful. Now a Yale-led research team has identified a new blocking mechanism that acts more like a dimmer switch and potently inhibits lung tumor cell growth.

Senior author Joseph Contessa and his co-authors screened hundreds of thousands of chemical compounds to uncover a new inhibitor that reduces the addition of sugar chains without harming non-tumor cells. Based on this finding, the research team plans to test the compound in preclinical studies as a potential new strategy for treating lung cancer — the leading cause of cancer death nationwide.