Genetic Targets to Chemo-Resistant Breast Cancer Identified

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

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

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

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

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

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

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

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

Liver Cancer Patients Can Start with Lower Dose of Chemotherapy and Live Just as Long

Penn study shows patients can benefit from fewer side effects and lower treatment costs

Patients with the most common type of liver cancer who are taking the chemotherapy drug sorafenib can begin their treatment with a lower dose than is currently considered standard, and it will not affect how long they live when compared to patients who start on the full dose. That finding comes from a new study from the Abramson Cancer Center of the University of Pennsylvania, published this week in the Journal of Clinical Oncology, and it opens the door for patients with hepatocellular carcinoma to begin with a reduced dose of sorafenib, which helps to minimize the drug’s side effects while also saving money for patients, providers, and insurers.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer among adults and is the second leading cause of cancer-related deaths worldwide. Currently, sorafenib is the only first-line treatment approved for HCC by the U.S. Food and Drug Administration, but its side effects can be particularly difficult on patients. A recent study found 85 percent of HCC patients taking the drug experienced adverse events. In 31 percent of patients on that study, the effects were severe enough to stop treatment. The standard dose sorafenib is 400mg, twice per day.

“Previous studies have started patients with half that dose, escalating only after the patients show they can handle it, but those studies have all been on a smaller scale,” said the study’s lead author Kim A. Reiss, MD, an assistant professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania. “We wanted to see if we could reproduce those results using a much larger cohort of patients.”

Reiss and her team used a Veterans Health Administration database and identified almost 5,000 HCC patients who were treated with sorafenib between 2006 and 2015, but they couldn’t do a side-by-side analysis of those who received a reduced dose versus those who received the full amount.

“One of the challenges that we faced was that the sickest patients tended to get the reduced dose because of concerns over how much they could tolerate, so any attempt to evaluate these groups based on how long they lived was skewed,” Reiss said.

To solve that problem, researchers looked at patient information to match people from each group based on disease stage, overall health, and other factors. That left them with two groups, each with 1,675 patients.

“Essentially, we used a computer model to simulate putting these patients into a randomized, controlled clinical trial,” said senior author David E. Kaplan, MD, MSc, an assistant professor of Gastroenterology and an associate professor of Medicine at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia.

The controlled data showed the reduced dose had no effect on overall survival. Patients starting at a lower dose had a median survival of 198 days, compared to 195 days for patients starting at the full dose.

In addition, about 40 percent of patients receiving the reduced dose escalated the drug amount within the first two months, while almost 12 percent of standard dose patients had to reduce their level within the same time period.

“It’s important to remember that the reduced dose patients will ramp up as they show they can handle it, while the full dose patients may have to ramp down because of these toxicities, so the dosage levels will converge in the middle,” Reiss said. “All of the patients get the treatment they need, but the reduced dose approach helps keep cost and toxicities down.”

The cost saving was significant. The study found the reduced dose patients took an average of about 100 fewer pills over the course of their treatment. That translated to an average savings of about $3,000 per patient. Reiss noted those numbers are based on VA prices, which tend to be lower than other centers, meaning the real savings for many patients could be even larger.

The researchers note that some doctors are already making use of this practice, which is why they were able to identify so many reduced dose patients for this study, but the majority of physicians are still starting with the full dose.

“Our data suggest starting at a reduced dose is a safe strategy that can be used more commonly,” Reiss said.

This study was supported by research funds from Bayer Healthcare Pharmaceuticals and the VA HIV, Hepatitis, and Related Conditions Programs in the Office of Specialty Care Services.

Long Term Survival Indicated for Advanced Stage Colorectal Cancer Patients who Survive at Least Two Years

Improvements in chemotherapy and liver surgery have resulted in increased overall survival in patients with advanced stage colorectal cancer in recent decades. In order to better predict outcomes for these patients, researchers at Rutgers Cancer Institute of New Jersey conducted a retrospective analysis and found that stage IV colorectal cancer patients who survived at least two years have a better prognosis than originally thought. Results of the work will be presented as part of a poster presentation at the American Society of Clinical Oncology Annual Meeting being held in Chicago early next month.

“With patients in this population living longer, it is imperative we refine prognostic information to more accurately predict survival.  This data will assist multi-disciplinary cancer management teams in making treatment decisions that ultimately will impact a patient’s quality of life,” notes Darren Carpizo, MD, PhD, surgical oncologist and director of the Hepatobiliary Program at Rutgers Cancer Institute and senior investigator of the work (pictured).

Investigators examined data on more than a thousand stage IV colorectal cancer patients seen at Rutgers Cancer Institute between 2005 and 2015. This included patients who had their cancer removed through surgery and were treated with follow-up therapies, as well as those patients who were not eligible for surgery. Complete data was available for 125 patients who survived for more than two years (75 had surgical removal of their cancer; 50 did not).  Median overall survival of patients who underwent surgery was not reached, while median overall survival for those who were not eligible for surgery was six years and three months.

“For those patients not eligible for initial surgery who survive two years, these findings indicate they may benefit from future surgery, if feasible, to treat remaining disease. For those patients who initially had surgery, this information may be helpful to identify patients who might benefit from repeat surgery to resect any recurrent metastatic disease,” adds Dr. Carpizo, who is also an associate professor of surgery and pharmacology at Rutgers Robert Wood Johnson Medical School.

Rutgers Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center. As part of Rutgers, The State University of New Jersey, Rutgers Cancer Institute is dedicated to improving the detection, treatment and care of patients with cancer, and to serving as an education resource for cancer prevention both at its flagship New Brunswick location and at its Newark campus at Rutgers Cancer Institute of New Jersey at University Hospital. Physician-scientists across Rutgers Cancer Institute also engage in translational research, transforming their laboratory discoveries into clinical practice that supports patients on both campuses.

New Ovarian Cancer Immunotherapy Study Poses Question: Can Microbiome Influence Treatment Response?

Roswell Park Study with pembrolizumab in untried combination is first ovarian cancer clinical trial to incorporate gut flora analysis

A new clinical study underway at Roswell Park Cancer Institute is the first to test the combination of the immunotherapy pembrolizumab with two other drugs as treatment for recurrent epithelial ovarian cancer, and is also the first ovarian cancer clinical trial to incorporate analysis of patients’ microbiomes — the bacteria present in the human gut and other organs.

This new study, led by Principal Investigator Emese Zsiros, MD, PhD, FACOG, Assistant Professor of Oncology in Roswell Park’s Department of Gynecologic Oncology and Center for Immunotherapy, is a phase II clinical trial that will enroll approximately 40 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, and will evaluate the impact of the combination of the PD1-targeting antibody pembrolizumab (Keytruda) with intravenous bevacizumab (Avastin) and oral cyclophosphamide (Cytoxan) on antitumor immune responses and on progression-free survival.

Pembrolizumab has been approved by the U.S. Food and Drug Administration for treatment of advanced melanoma, some metastatic non-small cell lung cancers and recurrent squamous cell head/neck carcinoma, but has only been tested in a small number of ovarian cancer patients, as a single drug and showing modest response. The investigators say a strong scientific rationale supports their hypothesis that the combination of pembrolizumab with two other drugs that have already been approved to treat ovarian cancer — bevacizumab and low-dose oral cyclophosphamide — may have much broader benefit for patients.

“Our biggest hope is that by trying these three drugs in combination, we can significantly extend the lives of patients with recurrent ovarian cancer. We also hope to minimize the side effects associated with chemotherapy drugs, and to markedly improve the quality of our patients’ lives,” says Dr. Zsiros. “We will be looking at potential biomarkers that will tell us who can most benefit from this therapy combination and to better understand how cancer cells and immune cells communicate with one another so that we can design better medications to kill cancer efficiently.“

As part of this study, the clinical team will analyze blood, tumor, stool, vaginal and skin microbiome samples, looking to identify possible associations between these markers with clinical outcomes and tumor response. The study, which is supported by a grant from Merck & Co. Inc., maker of pembrolizumab, will be one of the first to analyze these bacteria to determine possible associations with response to immunotherapeutic agents in patients with cancer.

“We’re looking at how to improve our immune defenses to cancer, but we’re looking at it from a variety of angles,” says Dr. Zsiros. “There’s a whole new area of research suggesting that what’s going on in our gut, our gut flora, has a huge influence on your overall health and happiness, and this study will extend that work into some new directions.”

According to the National Cancer Institute, epithelial ovarian cancer is one of the most common gynecologic malignancies, and is the fifth most frequent cause of cancer death in women.

 

Medulloblastoma Patients Should Receive Both Chemotherapy And Radiation Post-Surgery

In a recent study, a Yale Cancer Center team revealed that the addition of chemotherapy to postoperative treatment for adults with medulloblastoma improves survival. The benefit of chemotherapy, in addition to craniospinal radiation, was seen in adult patients with medulloblastoma (MB), including those with localized disease who received high-dose radiation treatment following surgery. The findings were presented September 26 at the American Society for Therapeutic Radiology (ASTRO) meeting in Boston.

Medulloblastoma is the most common brain tumor in children, but is relatively rare in adults. Chemotherapy use in adult MB is largely based on pediatric outcomes, and its effectiveness has been unclear.

This study used the National Cancer Data Base to identify 751 patients diagnosed with MB over the age of 18 who underwent surgical resection for MB and post-surgical radiation. Of the 751 patients, 520 (69.2%) received chemotherapy and radiation therapy and 231 (30.8%) received only radiation therapy. Estimated overall survival at five years was 14.5% higher for patients who received chemotherapy and radiation compared to patients who received radiation alone (86.1% versus 71.6%).

“Our analysis is the first to clearly demonstrate the improved survival that chemotherapy adds post-surgery for adult patients with medulloblastoma,” said Benjamin H. Kann, MD, first author on the study and a Resident in the Department of Therapeutic Radiology at Yale School of Medicine. “We can now confidently support the addition of chemotherapy to radiation therapy for our patients who can tolerate both treatments.”

Bristol-Myers Squibb Drug Fails Lung-Cancer Study

A blockbuster cancer treatment failed in a key study as the drug’s maker, Bristol-Myers Squibb, attempts to extend its usage for lung cancer patients.

Shares of the New York company plunged 16 percent Friday, its biggest one-day drop in 14 years. Shares of rival Merck & Co., which makes a rival cancer drug, spiked 10 percent to reach an 18-year high.

Bristol’s drug, Opdivo, and Merck’s drug Keytruda are immunotherapies, which bolster the immune system so that patients can better fight cancer. Both drugs are already approved to treat melanoma and lung cancer, but only after chemotherapy.

In June, Merck reported positive results from a key study focusing on Keytruda as a lone treatment for lung cancer. The negative results from Bristol appear to put Merck in the lead for treating cancer patients without resorting to chemotherapy and its drastic side effects.

The latest late-stage study for Opdivo involved 541 patients who had received no prior treatment for lung cancer.

“We remain committed to improving patient outcomes through our comprehensive development program,” said Bristol-Myers CEO Dr. Giovanni Caforio.

-Associated Press

Restoring Chemotherapy Sensitivity by Boosting MicroRNA Levels

By increasing the level of a specific microRNA (miRNA) molecule, researchers have for the first time restored chemotherapy sensitivity in vitro to a line of human pancreatic cancer cells that had developed resistance to a common treatment drug.

If the miRNA molecules can be delivered to cells in the human body – potentially with nanoparticles – the technique might one day be used to battle the chemotherapy resistance that often develops during cancer treatment. A research team at the Georgia Institute of Technology identified the miRNA used in the research with a computer algorithm that compared the ability of different miRNAs to control the more than 500 genes that were up-regulated in drug-resistant cancer cells.

The study was scheduled to be reported May 27 in the Nature Publishing Group journal Cancer Gene Therapy.

“We were specifically interested in what role miRNAs might play in developing drug resistance in these cancer cells,” said John McDonald, a professor in Georgia Tech’s School of Biology and director of its Integrated Cancer Research Center. “By increasing the levels of the miRNA governing the suite of genes we identified, we increased the cells’ drug sensitivity back to what the baseline had been, essentially undoing the resistance. This would suggest that for patients developing chemotherapy resistance, we might one day be able to use miRNAs to restore the sensitivity of the cancer cells to the drugs.”

MicroRNAs are small non-coding molecules that function in RNA silencing and post-transcriptional regulation of gene expression. The miRNAs operate via base-pairing with complementary sequences within messenger RNA (mRNA) molecules, silencing the mRNA molecules that control the expression of certain proteins.

Roman Mezencev, a senior research scientist in the McDonald lab, began by exposing a line of pancreatic cancer cells (BxPC3) to increasing levels of the chemotherapy drug cisplatin. After each in vitro treatment, surviving cells were allowed to proliferate before being exposed to a higher level of the drug. After approximately a year and 20 treatment cycles, the resulting cell line had a resistance to cisplatin that was 15 times greater than that of the original cancer cells.

The next step was to study the genetic changes associated with the resistance, comparing levels of more than 2,000 miRNAs in the cisplatin-resistant line to the original cell line that had not been exposed to the drug. Using a hidden Markov model (HMM) algorithm, they found 57 miRNAs that were either up-regulated or down-regulated, and identified miR-374b as the molecule most likely to be controlling the genes that govern chemotherapy resistance.

While previous work by other researchers has shown that miRNAs can provide a mechanism for the development of drug resistance, the Georgia Tech team took the findings a step farther by increasing the expression of miR-374b. When they did, they found that the cells previously resistant to the cisplatin were again sensitive to the drug – almost back to their original levels.

Techniques to control protein expression are already being used in cancer therapy, but McDonald believes there may be benefits in targeting the activity higher up in the process – at the RNA level. Studies by the Georgia Tech team and by other researchers clearly show an association between chemotherapy resistance and changes in levels of certain miRNAs.

“Molecular evolution is a highly efficient process,” McDonald said. “Our evidence suggests that many of the genes regulated by a single microRNA are involved in coordinated cellular functions – in this case, drug resistance. We believe that microRNAs might be particularly good cancer therapeutic agents because when we manipulate them, we are manipulating suites of functionally coordinated genes.”

A next step will be to study the effects of manipulating miRNA levels in animal cancer models. The McDonald research team is currently pursuing this possibility by inserting the microRNAs into tumors using nanoscale hydrogels developed by Andrew Lyon, former chair of Georgia Tech’s School of Chemistry and Biochemistry.

McDonald says the study confirms the role of miR-374b in creating resistance, though he says there could be other microRNA molecules involved, as well.

“These cells have acquired resistance to the drug, and we have found a microRNA that seems to be playing a major role,” he said. “We have shown that we can bring sensitivity to drugs back by restoring levels of miR374b, but there may be other miRNAs that will work equally as well. Just as there are multiple pathways to establish cancer and chemoresistance, there may be multiple pathways to restore chemosensitivity, as well.”

If cancer could one day be treated using miRNAs, it’s likely to be a continuing battle rather than a decisive victory, McDonald said. Cancer cells are very resourceful, and will likely find a new genetic route to resistance if one pathway is destroyed. That could require use of a different miRNA to reverse resistance.

While the miRNA research isn’t likely to provide a “magic bullet” for cancer, it does show the possible role of these tiny RNA molecules in controlling a broad class of bodily processes.

“There is growing evidence that this class of small regulatory RNAs may be involved in many processes ranging from evolution to heart disease,” he said. “MiRNAs are emerging as important players in cancer in general. Here, we are focusing on just one particular aspect of it.”

Cancer Immunotherapies take Center Stage

The newly created task force on cancer, in what Vice President Joe Biden has called a “moon shot” to cure the disease, is to put the US on a path to achieve in just five years research and treatment that otherwise might take a decades or more.  Although the memorandum does not commit the government to major new spending, the task force’s role will be to focus on making the most of federal investments, targeted incentives, private sector efforts from industry and philanthropy, patient engagement initiatives and other mechanisms to support cancer research and enable progress in treatment and care.

One area of promise in oncology, has been cancer immunotherapy, which harness the power of the immune system to eradicate cancer and prime the immune system to fight off relapses. For decades, most cancers have been treated with the standard of care treatments which typically include surgery, radiation and/or chemotherapy.

Immunotherapy is a wide area of cancer treatment and research that has built momentum in recent years. Many different types of immunotherapies have been effective in treating and even potentially curing melanomas, B-cell Chronic lymphocytic leukemia, and non-Hodgkin lymphoma, and are currently being developed to treat nearly every time of cancer, including breast cancer. Recent research showed that 70 percent of multiple myeloma patients recovered with immunotherapy.

New Thinking in Head & Neck Cancer

CEL-SCI Corporation, a Vienna-based biotech firm is currently investigating their flagship investigational cancer immunotherapy, Multikine (Leukocyte Interleukin, Injection), in a global Phase 3 clinical study  in head and neck cancers, in what they believe is the logical next step in immunotherapy development. Based on the results of earlier human studies, researchers at CEL-SCI believe that cancer  immunotherapy should be administered as an initial therapy before a patient’s immune system has been debilitated by surgery, radiation and chemotherapy. Data from earlier Multikine Phase 2 human studies, demonstrated that when Multikine was administered for only 3 weeks immediately after diagnosis, the treatment reduced and in some cases eliminated all signs of a tumor before surgery, radiation and/or chemotherapy, for head and neck cancer patients, were administered.

Other investigational cancer treatments and immunotherapies are usually tested as a last resort on patients who have already undergone and failed standard of care treatments. Therapies which are used as a last resort and show some efficacy, will have reached their clinical study primary endpoint in a fairly short period of time. That is because patients with end-stage disease generally have a shorter life expectancy.

The company is the first to advance its investigational cancer immunotherapy into Phase 3 studies where it is actually administered as a first-line treatment immediately after diagnosis within a three-week window before any standard-of-care treatments. Most other cancer immunotherapy treatment regimens must be administered over longer periods of time and cannot be given in the brief three-week period before the current standard of care (surgery and/or radiation and chemotherapy) must be administered. If this treatment regimen is proven successful, the drug will, (1) reduce the number of cancer recurrences and, (2) increased the overall survival of the patients who were treated with the drug.

The hope is that someday Multikine will be administered as the first treatment right after initial cancer diagnosis for many different types of cancers.