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Researchers Developing New Targeted and Immune Therapies for Colorectal Cancer Molecular Subtypes

May 27, 2015

CHICAGO (May 27, 2015) — Medical oncology is a rapidly evolving field, and oncology-related precision medicine—or the matching of treatments to a specific patient and their cancer—is at the forefront of this evolution. Researchers from Fox Chase Cancer Center in Philadelphia recently collaborated with Caris Life Sciences®, a biotechnology company headquartered in Dallas-Fort Worth, Texas, to conduct three separate studies related to precision medicine, particularly in colorectal cancers. These findings will be highlighted at the upcoming 2015 American Society of Clinical Oncology Annual Meeting.

Colon or rectal cancer can now be classified as one of several molecular subtypes that are treated differently. As a result, therapy has improved for patients with advanced disease who have historically been difficult to treat. In some cases, oncologists can now avoid treatments predicted not to work and can focus only on those shown to improve outcomes.

“There is exciting progress in the treatment of colorectal cancer. Understanding the impact of genetic mutations on the potential likelihood of response to new treatments helps pave the way for defining their optimal use,” said Wafik El-Deiry, MD, PhD, FACP, a practicing physician-scientist who specializes in colorectal cancer treatment. He also serves as deputy cancer center director for translational research and co-leader of the Molecular Therapeutics Program at Fox Chase.

Abstract #152887

Lead study author Namrata Vijayvergia, MD, a senior fellow in hematology/oncology at Fox Chase, and the research team profiled 55 patients with microsatellite-instable colorectal cancer—a special subtype of colorectal cancer—at Caris Life Sciences. Tested biomarkers included the ones that may predict patient response to various therapeutic agents based on published clinical studies. The researchers analyzed results based on programmed death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression that may predict response to immune checkpoint inhibitor therapies.

Analysis of 55 tumors revealed 39 (71%) had higher expression of PD-1 and PD-L1 [P (+)]. Expression of various other biomarkers were not significantly different in the P(+) and P(-) group. Transducing-like enhancer of split 3 (TLE-3) protein expression, however, was higher in the P(+) group [43% in P(+) and only 8% in P(-) microsatellite-instable tumors.  Only 9 (27%) of P(+) tumors harbored a KRAS mutation, whereas 10 (62%) had KRAS mutation in P(-) tumors.

“In this particular study, we aimed to look at molecular abnormalities that may correlate with PD-1 expression on tumor-infiltrating lymphocytes in microsatellite-instable colorectal cancers and identified KRAS mutation to be inversely associated with the PD-1 expression,” Dr. Vijayvergia said. “This is relevant to clinical trials testing immune checkpoint inhibitors in this subset of patients, where they may have promising activity.”  

Abstract #152736

Elena Shagisultanova, MD, lead study author and fellow in hematology/oncology at Fox Chase, and her team profiled 26 microsatellite-instable and 558 non-microsatellite–instable colorectal cancers to gain insight into biology of these tumors and to find new treatment methods for resistant cancers. Mutations in two important genes—BRCA1 and BRCA2—were significantly more common in colorectal tumors with microsatellite instability compared to tumors without. BRCA1 and BRCA2 proteins participated in repairing of the DNA of the cells, according to the researchers. Mutations in BRCA1 and BRCA2 genes may make tumor cells more sensitive to the drugs, producing “breaks” in the DNA, such as mitomycin C and PARP inhibitors. These agents could be tried in patients with microsatellite instability–positive colorectal carcinomas.

Most of the tumors with microsatellite instability that had mutations in the BRCA genes also had an increased level of the protein c-MET, a receptor on the cell surface that signals the cells to divide and grow. Blocking c-MET with targeted inhibitors may help suppress the growth of microsatellite instability–positive colorectal tumors. “Based on our results, we suggest therapy with c-MET inhibitors combined with mitomycin C or PARP inhibitors for further testing in colorectal tumors with microsatellite instability,” Dr. Shagisultanova said.

Abstract #151145

Lead study author Zoran Gatalica, MD, medical director at Caris Life Sciences, and the other researchers assessed 64 microsatellite-instable, 9 low microsatellite instability, and 558 microsatellite-stable cases at Caris Life Sciences using immunohistochemistry—a technique used to detect protein expression in tissue samples—and sequencing. Compared with non-microsatellite instable tumors, microsatellite-instable tumors had significantly higher expression of TS, PTEN expressions and significantly higher mutation rates of BRAF, CTNNB1, HNF1A, BRCA1 and BRCA2. Microsatellite-instable cancers were also significantly more often infiltrated with PD-1+ lymphocytes, according to the researchers.

"Caris Life Sciences is proud to continue a collaborative relationship with Dr. El-Deiry and Fox Chase Cancer Center that has yielded a deeper understanding of microsatellite-instable colorectal cancer biology,” said Dr. Gatalica. “We believe that identification of biomarkers associated with conventional, targeted, as well as immune-modulatory therapies achieved through a comprehensive profiling will lead to optimal individualized treatment of colorectal cancers.”

Dr. El-Deiry has collaborated with Caris Life Sciences for several years on colorectal cancer genomic profiling and is a strong proponent of innovation in precision medicine testing. He added, “As we continue to recognize and define specific molecular subtypes within colorectal cancer and receive insights into which patients are most likely to benefit from our new treatments, we can offer precise targeted therapy options for our patients with aggressive disease. This is exciting collaborative translational research that involves going back and forth from the lab to the clinic.”

       

The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.
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