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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Accelerating the Development of Next-Generation Cancer Therapies

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

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

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

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

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

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

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

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

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

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

About The Gene Editing Institute

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

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

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

Study Suggests that Zika Virus Could Be Used to Treat Brain Cancer Patients

Recent outbreaks of Zika virus have revealed that the virus causes brain defects in unborn children. But in a study to be published September 5 in The Journal of Experimental Medicine, researchers from Washington University School of Medicine in St. Louis and the University of California, San Diego report that the virus could eventually be used to target and kill cancer cells in the brain.

Glioblastoma is the most common form of brain cancer and is frequently lethal; most patients die within two years of diagnosis. Just like normal, healthy tissues, the growth and development of glioblastomas is driven by stem cells that proliferate and give rise to other tumor cells. Glioblastoma stem cells are hard to kill because they can avoid the body’s immune system and are resistant to chemotherapy and radiation. But killing these cells is vital to prevent new tumors from recurring after the original tumor has been surgically removed.

“It is so frustrating to treat a patient as aggressively as we know how, only to see his or her tumor recur a few months later. We wondered whether nature could provide a weapon to target the cells most likely responsible for this return,” says Milan Chheda from Washington University School of Medicine in St. Louis.

One approach to killing cancer stem cells involves using viruses that specifically target tumor cells. Zika virus appears to disrupt fetal brain development by preferentially targeting neural stem and progenitor cells. The virus’ effects on adult brains—which contain fewer active stem cells that developing fetal brains—are generally much less severe.

“We hypothesized that the preference of Zika virus for neural precursor cells could be leveraged against glioblastoma stem cells,” says Michael Diamond, also from Washington University School of Medicine in St. Louis, who co-directed the study with Milan Chheda and with Jeremy Rich, from the University of California, San Diego and the Cleveland Clinic Lerner Research Institute.

The researchers found that Zika virus preferentially infected and killed patient-derived glioblastoma stem cells compared with other glioblastoma cell types or normal neural cells. When mice with aggressive glioma were injected with a mouse-adapted strain of Zika virus, the virus slowed tumor growth and significantly extended the animals’ lifespan.

The researchers then tested a mutant strain of Zika that is less virulent than naturally occurring strains of the virus. This “attenuated” strain, which is more sensitive to the body’s immune response, was still able to specifically target and kill glioblastoma stem cells and was even more effective when combined with a chemotherapy drug, temozolomide, that usually has little effect on these cells. “This effort represents the creative synthesis of three research groups with complementary expertise to attack a deadly cancer by harnessing the cause of another disease,” says Jeremy Rich. “Adults with Zika may suffer less damage from their infection, suggesting that this approach could be used with acceptable toxicity.”

“Our study is a first step towards the development of safe and effective strains of Zika virus that could become important tools in neuro-oncology and the treatment of glioblastoma,” says Diamond. “However, public health concerns will need to be addressed through pre-clinical testing and evaluations of the strains’ ability to disseminate or revert to more virulent forms.”

A blood test can predict early lung cancer prognosis

Cancer cells obtained from a blood test may be able to predict how early-stage lung cancer patients will fare, a team from the University of Michigan has shown.

This information could be used to determine which patients are most likely to benefit from additional therapies to head off the spread of the cancer to other areas of the body.

With a new single cell analysis service in U-M’s Comprehensive Cancer Center, the researchers are making the necessary technology more widely available in the university system. They hope these “liquid biopsies” will be offered to patients within the next five years.

Circulating tumor cells, representing only about one in a billion cells in the bloodstream, are largely untapped sources of information about tumors, but new methods are bringing their diagnostic value ever closer to patient care.

Sunitha Nagrath, U-M professor of chemical engineering who designs devices that can capture these rare cells, led a team including oncologists and surgeons to explore how cancer cells escape tumors and travel through the body in the bloodstream. This is how metastases, or satellite tumors elsewhere in the body, are thought to form.

“The tumors were constantly shedding cells even when they were small–that’s one thing we learned,” Nagrath said. “Although we define the tumors as early stage, already they are disseminating cells in the body.”

Early-stage lung cancer patients, whose tumors may only measure a few millimeters in diameter, are typically treated with surgical removal of the tumor, but the study results suggest that this may not be enough. A handful of patients had tumors that were shedding hundreds or thousands of tumor cells into the lung.

“Even though you removed the tumor, you left behind these hundreds and hundreds of cells,” Nagrath said. “If you know this patient walking out of the clinic is going to relapse after less than a year because of these cells, why don’t we treat them now?”

With a relatively small sample of 36 patients, the team can’t definitively say that an actively shedding tumor will lead to metastasis within a year, but Nagrath is exploring the predictive power of cancer cells drawn from the blood. In particular, the study showed that clusters of two or more tumor cells indicated shorter survival times. Six of the nine patients whose cancer returned during the two to 26 months of follow-up had circulating tumor cells appearing in clusters.

“Ultimately, this method will help us look for and find potential markers for either metastatic spread or cancer detection,” said Rishindra Reddy, U-M associate professor of surgery who coordinated the blood samples and designed the study with Nagrath and Nithya Ramnath, an associate professor of medical oncology at the U-M Medical School.

Gangs of aggressive cells

Genetic analysis confirmed that clusters showed higher expression of aggressive traits. They were better at moving, evading the immune system, recruiting blood cells to help them and resisting treatments. In other words, clustered tumor cells were better suited to spreading cancer to distant locations.

“These are drivers of tumor progression and resistance, and they are more important to target with therapy,” Nagrath said.

To gather the data underpinning these findings, the team took blood samples before, during and after tumor removal surgery. At each stage, surgeons collected blood from a vein in the patient’s arm, far from the tumor. Early in surgery, before disturbing the tumor, the surgeon also drew blood from the lung vein that drained from the tumor, where tumor cells are expected to be more concentrated.

And they were–as Vasudha Murlidhar, then a doctoral student in the Nagrath lab, showed by analyzing all the samples using a microfluidic chip of her own design. While tumor cells from the arm had a median count of around 1.3 per 3 milliliters, it was 7.5 per 3 ml of blood from the lung. Among the patients whose lung blood samples revealed hundreds or even thousands of tumor cells, the numbers fell sharply by the time the cells reached the vein in the arm.

It couldn’t be explained by mere dilution. The researchers hypothesize that the larger clusters are getting stuck in capillaries–potentially the start of a new tumor–or that many of these cells can’t survive in the bloodstream.

Toward monitoring cancer with blood tests

Nagrath is impatient to see liquid biopsy begin to benefit patients at U-M. Already, this study demonstrates that capturing cancer cells from the bloodstream can indicate which patients are most in need of a second treatment, such as chemotherapy, to go after the cells that have already dispersed in the body. It could also help doctors choose drugs that will be better at exploiting the weaknesses of these aggressive cells.

Nagrath is advancing the technology at U-M by co-directing a new service arm within the Cancer Center. The new Single Cell Analysis Core will isolate cancer cells from blood using many different microfluidic chips, developed by Nagrath’s group and others.

Evan Keller, a professor of urology in the Medical School, will lead the cell analysis techniques. This effort will primarily help cancer researchers better understand the disease for now, but Nagrath is hopeful that it won’t be long before liquid biopsies are part of routine patient care at Michigan Medicine.

“With a simple blood draw, we can tell the dynamic state of the disease during the treatment and after the treatment, monitoring it closely. If something has to show up on a CT scan, it may already be too late,” Nagrath said.

The study is titled “Poor prognosis indicated by venous circulating tumor cell clusters in early stage lung cancers” and will appear in Cancer Research.

The microfluidic chips for isolating cancer cells were produced at the Lurie Nanofabrication Facility at U-M. Captured cells were analyzed with the help of the Microscopy and Image Analysis Laboratory and the Cancer Center’s DNA Sequencing Core at U-M. This study was funded by the National Institutes of Health Director’s New Innovator Award, the U-M Lefkofsky Scholarship and the U-M Rackham International Student Fellowship.

Vasudha is now a postdoctoral scholar in biomedical engineering at the University of California, Davis.

Novartis garners first ever FDA approval for a CAR-T cell therapy, Kymriah(TM), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice

Novartis announced today that the US Food and Drug Administration (FDA) has approved Kymriah(TM)(tisagenlecleucel) suspension for intravenous infusion, formerly CTL019, the first chimeric antigen receptor T cell (CAR-T) therapy, for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah is the first therapy based on gene transfer approved by the FDA.

“At Novartis, we have a long history of being at the forefront of transformative cancer treatment,” said Joseph Jimenez, CEO of Novartis. “Five years ago, we began collaborating with the University of Pennsylvania and invested in further developing and bringing what we believed would be a paradigm-changing immunocellular therapy to cancer patients in dire need. With the approval of Kymriah, we are once again delivering on our commitment to change the course of cancer care.”

The FDA has approved a Risk Evaluation and Mitigation Strategy (REMS) for Kymriah. The REMS program serves to inform and educate healthcare professionals about the risks that may be associated with Kymriah treatment. To support safe patient access, Novartis is establishing a network of certified treatment centers throughout the country which will be fully trained on the use of Kymriah and appropriate patient care.

There has been an urgent need for novel treatment options that improve outcomes for patients with relapsed or refractory (r/r) B-cell precursor ALL, whose prognosis is poor. Patients often undergo multiple treatments including chemotherapy, radiation, targeted therapy or stem cell transplant, yet less than 10% of patients survive five years [2], [3].

Kymriah is an innovative immunocellular therapy that is a one-time treatment. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence. In 2012, Novartis and the University of Pennsylvania (Penn) entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

“This therapy is a significant step forward in individualized cancer treatment that may have a tremendous impact on patients’ lives,” said Carl June, MD, the Richard W. Vague Professor of Immunotherapy, Director of the Center for Cellular Immunotherapies in Penn’s Perelman School of Medicine, who is a pioneer of this new treatment. “Through our collaboration with Novartis, we are creating the next wave of immunocellular cancer treatments, and are eager to progress CAR-T therapy in a host of hematologic and other cancer types.”

In close collaboration with Novartis and Penn, Children’s Hospital of Philadelphia (CHOP) was the first institution to investigate Kymriah in the treatment of pediatric patients leading the single site trial.

“Tisagenlecleucel is the first CAR-T therapy to demonstrate early, deep and durable remission in children and young adults with relapsed or refractory B-cell ALL,” said Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at Penn, and Director of the Cancer Immunotherapy Frontier Program at Children’s Hospital of Philadelphia (CHOP). “We’ve never seen anything like this before and I believe this therapy may become the new standard of care for this patient population.”

Novartis is committed to ensuring eligible patients have access to Kymriah, and is working to ensure payers understand the value of Kymriah and provide coverage for patients. To address the unique aspects of the therapy, Novartis has also developed various patient access programs to support safe and timely access for patients. Novartis is also providing traditional support to patients by helping them navigate insurance coverage and providing financial assistance for those who are uninsured or underinsured.

Novartis plans additional filings for Kymriah in the US and EU later this year, including applications with the FDA and European Medicines Agency (EMA), for the treatment of adult patients with r/r diffuse large B-cell lymphoma (DLBCL). Additional filings beyond the US and EU are anticipated in 2018.

Spider peptides battle superbugs and cancer

As antibiotic resistance rises and fears over superbugs grow, scientists are looking for new treatment options. One area of focus is antimicrobial peptides (AMPs), which could someday be an alternative to currently prescribed antibiotics, many of which are becoming increasingly useless against some bacteria. Now, a team reports in ACS Chemical Biology that they have improved the antimicrobial — and anticancer — properties of an AMP from a spider.

According to the U.S. Centers for Disease Control and Prevention, 2 million people become infected with antibiotic-resistant bacteria in the U.S. each year. Because no known antibiotics work against these bacteria, patients simply have to hope that their natural defenses eventually overcome the infection. But some patients experience severe symptoms, landing them in a hospital, and in extreme cases, they could die. Researchers are trying to find alternatives to traditional antibiotics, and one such possibility is a group of peptides called AMPs. These peptides are found in all plants and animals as a type of immune response and have been shown to be potent antibiotics in the laboratory. Gomesin, an AMP from the Brazilian spider Acanthoscurria gomesiana can function as an antibiotic, but it also has anticancer activity. When gomesin was synthesized as a circle instead of as a linear structure, these characteristics were enhanced. Sónia Troeira Henriques and colleagues wanted to further boost the peptide’s traits.

The team made several variations of the cyclic gomesin peptide and found that some of these were 10 times better at killing most bacteria than the previously reported cyclic form. In other experiments, the new AMPs specifically killed melanoma and leukemia cells, but not breast, gastric, cervical or epithelial cancer cells. The researchers determined that the modified peptides killed bacteria and cancer cells in a similar way — by disrupting the cells’ membranes. The group also notes that the modified AMPs were non-toxic to healthy blood cells.

Prostate Cancer Cells Become ‘Shapeshifters’ to Spread to Distant Organs

Johns Hopkins Kimmel Cancer Center scientists report they have discovered a biochemical process that gives prostate cancer cells the almost unnatural ability to change their shape, squeeze into other organs and take root in other parts of the body. The scientists say their cell culture and mouse studies of the process, which involves a cancer-related protein called AIM1, suggest potential ways to intercept or reverse the ability of cancers to metastasize, or spread.

Results of the research are described in the July 26 issue of Nature Communications.

For the study, the Johns Hopkins scientists mined publically available research data on the genetics and chemistry of hundreds of primary and metastatic cancers included in five studies of men with prostate cancer. They found that a gene called AIM1 (aka “absent in melanoma 1”), which makes proteins also called AIM1, is deleted in approximately 20 – 30 percent of prostate cancers confined to the gland and about 40 percent of metastatic prostate cancers. In addition, the scientists found, on average, two- to fourfold less amounts of AIM1 expression in metastatic prostate cancers compared with normal prostate cells or those from men with prostate cancers confined to the prostate, suggesting that reduction of AIM1 proteins is somehow linked to tumor spread.

Aside from its link to the development of melanoma, a deadly skin cancer, scientists knew little about the function of AIM1.

“Our experiments show that loss of AIM1 proteins gives prostate cancer cells the ability to change shape, migrate and invade. These abilities could allow prostate cancer cells to spread to different tissues in an animal and presumably a person,” says Michael Haffner, M.D., Ph.D., a pathology resident and former postdoctoral fellow at the Johns Hopkins Kimmel Cancer Center who is involved in the research. “It’s not the whole story of what is going on in the spread of prostate cancer, but it appears to be a significant part of it in some cases.”

Looking more closely at the AIM1 gene and its protein levels in prostate cancer tissues, the Johns Hopkins scientists found that many times, even when the gene isn’t completely deleted and its protein production is reduced, its location in the prostate cancer cell is highly abnormal compared with normal prostate cells. This occurs even in primary prostate cancer cells, which have invaded the local structures to form invasive cancer within the prostate gland, say the scientists.

The research team used dyes to track the location of AIM1 proteins in human cells grown in the lab and followed where they appear in normal and cancerous prostate tissues. In normal prostate cells, AIM1 was located along the outside border of each cell and paired up with a protein called beta-actin that helps form the cell’s cytoskeleton, or scaffolding. However, in prostate cancer cells, the protein spread away from the outer border of the cells and no longer paired up with beta-actin.

The scientists found this pattern among a set of human prostate tissue samples including 81 normal prostates, 87 localized prostate cancers and 52 prostate cancers that had spread to the lymph nodes.

“It appears that when AIM1 protein levels drop, or when it’s abnormally spread throughout the cell instead of confined to the outer border, the prostate cancer cells’ scaffolding becomes more malleable and capable of invading other tissues,” says Vasan Yegnasubramanian, M.D., Ph.D., associate professor at the Kimmel Cancer Center and a member of the research team. With AIM1, the scaffold, Yegnasubramanian says, keeps normal cells in a rigid, orderly structure. Without AIM1, cells become more malleable, shapeshifting nomads that can migrate to other parts of the body, he says.

To track how these shapeshifting cancer cells move, the Johns Hopkins scientists, with Steven An, Ph.D., an expert in cellular mechanics and an associate professor at the Johns Hopkins Bloomberg School of Public Health, took a close-up look at AIM1-lacking prostate cancer cells, using sophisticated and quantitative single-cell analyses designed to probe the material and physical properties of the living cell and its cytoskeleton.

They found that cells lacking AIM1 remodeled their scaffolding more than twice as much as cells that had normal levels of AIM1, and that they exert three- to fourfold more force on their surroundings than cells with normal levels of the protein. Such cellular properties are reminiscent of cells with high potential to invade and migrate, An notes.

In addition, the scientists found that AIM1-lacking prostate cells were capable of migrating to unoccupied spaces on a culture dish or invading through connective tissue-like materials at rates fourfold higher than cells with normal levels of AIM1.

Next, the scientific team implanted human prostate cancer cells engineered without AIM1 in five mice and found that the cells spread to other tissues at levels 10 to 100 times more than cells with normal levels of AIM1 that were implanted in five similar mice. However, the AIM1-lacking cells were not able to establish full colonies and tumors at those other tissues, suggesting that AIM1 depletion is not the whole story in the spread and growth of metastatic prostate cancer.

“AIM1 may help prostate cancer cells disseminate throughout the body, but something else may be helping them form full-blown metastatic tumors when they get there,” says Yegnasubramanian.

The Johns Hopkins scientists plan to further study what happens to the AIM1 protein to cause its abnormal location in prostate cancers and identify other proteins and genes that work with AIM1 to cause metastasis. Such studies could help scientists find new drug targets aimed at preventing or reversing prostate metastasis.

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.