VARI-SU2C Epigenetics Dream Team supports new clinical trial that targets metastatic colorectal cancer

The first clinical trial to move forward as part of the Van Andel Research Institute-Stand Up To Cancer (VARI-SU2C) Epigenetics Dream Team will target metastatic colorectal cancer, the second leading cause of cancer deaths among men and women combined in the U.S.

Nationally, an estimated 132,700 people were diagnosed with colorectal cancer in 2015, according to the U.S. Centers for Disease Control and Prevention. The high mortality rate is due in part to colorectal cancer's tendency to aggressively spread, or metastasize, to other organs. To better combat these metastatic cancers, scientists have turned to promising new epigenetic therapies that have potential to directly treat cancer or to sensitize tumors to traditional treatments.

"The first SU2C Epigenetics Dream Team made significant progress in treating some lung cancers, finding that epigenetics can potentially 'prime' cancer cells, making them more receptive to subsequent chemo and/or immunotherapy," said SU2C Co-founder Katie Couric. "I'm excited that the new VARI-SU2C Epigenetics Dream Team will work to build on those results, potentially bringing new hope to patients with colorectal cancer through this trial."

The trial is led by VARI-SU2C Epigenetics Dream Team members Nilofer Azad, M.D., and Nita Ahuja, M.D., at Johns Hopkins University's Sidney Kimmel Comprehensive Cancer Center, with scientific oversight and support provided by the Dream Team. Phase I has been underway since 2013; by conducting the next phase of the trial through the Dream Team, investigators will be able to add 40 more patients to phase II and perform additional specimen collection and analysis. These enhancements will provide a more thorough look into the efficacy of a potential new treatment for metastatic colorectal cancer.

"We're thrilled to support this promising trial as part of the VARI-SU2C Epigenetics Dream Team," said Peter Jones, Ph.D., D.Sc., Dream Team co-leader and VARI's research director. "Through this collaboration, we have an exceptional opportunity to further develop the next generation of epigenetic cancer therapies. The initial results from phase I were very encouraging and we look forward to the results of phase II."

The phase II trial will further test a combination therapy that includes a drug called guadecitabine (SGI-110), which corrects errors in methylation, a common epigenetic process that determines whether a gene is switched on or off. Genes that are inappropriately switched off do not produce proteins needed for normal function and can contribute to diseases such as cancer.

Phase II began enrolling patients in January. Although the trial is based at Johns Hopkins, clinical work will also occur at University of Southern California and Memorial Sloan Kettering Cancer Center--both Dream Team institutions--as well as VU University Medical Center in the Netherlands. Guadecitabine is supplied by Astex Pharmaceuticals, Inc.

Recent data suggest mutations in certain genes can be used to predict resistance to many common chemotherapies. Patients with these mutations are often first treated with a drug called irinotecan, followed by additional drug therapies if the cancer becomes desensitized to the initial treatment. Although first-line drugs like irinotecan are about 60 percent effective, efficacy for second and third line therapies drops to 10 percent and less than 5 percent, respectively. Ahuja's laboratory has shown that the use of demethylating drugs like guadecitabine can sensitize resistant colorectal cancer cell lines and tumors to irinotecan therapy. The team is now testing the hypothesis that the use of guadecitabine will re-sensitize patients to irinotecan, and allow for a better response and survival rate compared to current second and third line therapies.

"Being part of the VARI-SU2C Epigenetics Dream Team allows this exciting work to move forward quickly in patients," Azad said. "In particular, it allows us to test these drugs in enough patients to really have a strong sense if these drugs work for people with colorectal cancer."

Working through the Dream Team also allows investigators to gather additional samples from patients for further analysis, which will provide a deeper insight into colorectal cancer and metastasis.

"We're now able to collect additional biopsy tissues from the patients so that we can better understand how these therapies work using cutting-edge genomic studies," Ahuja said. "This kind of correlative work allows us to continuously improve our understanding of cancer."