VARI-SU2C Epigenetics Dream Team Progress Update
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The VARI-SU2C Epigenetics Dream Team Progress Report
Funding: $7.5 million
Leader: Peter A. Jones, PhD, DSc, Van Andel Research Institute
Co-Leader: Stephen B. Baylin, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Fast Facts on metastatic colorectal cancer, acute myeloid leukemia, and myelodysplastic syndrome:
- Metastatic colorectal cancer (mCRC) is the second leading cause of cancer death in the United States.
- In mCRC cancerous cells formed in the colon or rectum spread to other parts of the body. It is named after the part of the body where the cancer originated.
- Acute myeloid leukemia (AML) affects cells that would normally develop into different blood cells. AML originates in the bone marrow, where blood cells are made.
- The term “acute” means that is progresses quickly and can be fatal, if not effectively treated.
- Myelodysplastic syndrome (MDS) occurs when the bone marrow does not produce enough healthy blood cells.
- Roughly 30% of MDS cases will progress to AML.
The Pediatric Cancer Dream Team’s Research Project
Epigenetic describes biological processes that cells use to control whether genes are turned on or off without altering the DNA sequence itself. Building on the successes of the original SU2C Epigenetics Dream Team, the Van Andel Research Institute (VARI)-SU2C Epigenetics Dream Team is continuing their focus on applying epigenetic therapies to multiple types of cancers.
Colorectal Cancer: In 2015, an estimated 132,700 Americans will be diagnosed with colorectal cancer and of those, 49,700 will die. Only 13 percent of people survive five years or longer (5-year survival rate) after the original cancer has spread to distant organs. Even after treatment, colorectal cancer may recur depending on the stage of the cancer before treatment. With limited treatment options the Dream Team is pursuing a specific combination of drugs to treat metastatic colorectal cancer (mCRC) with hopes that more people will respond and survive their cancer.
Acute Myeloid Leukemia (AML) and myeloid dysplastic syndrome (MDS): AML is fatal if not properly treated and there are few effective treatments especially for advanced disease. The 5-year survival rate for AML patients is 25%. A particular group of AML patients whose prognoses are unfavorable are those individuals with the bone marrow disorder MDS. New therapies are needed, especially for patients that do not respond well the current, available chemotherapy regimens. The Dream Team is pursuing a specific combination of drugs to treat AML with hopes that more people will respond and survive their cancer.
This Dream Team is investigating a novel drug, SGI-110, which belongs to a class of epigenetic drugs called DNA methyltransferase inhibitors (DNMTis). This Team is exploring the potential of this DNMTis in patients with advanced colon cancer who have developed resistance to the drug irinotecan. In colon cancer patients SGI-110 is being combined with irinotecan, which blocks growth, while in AML patients SGI-110 is being combined with drugs called PARP inhibitors that kill cancer cells by blocking repair of DNA. Finally, the Dream Team plans to test whether DNMTis will sensitize AML/MDS patients to immunotherapy with atezolizumab, which blocks immune checkpoint molecules that are used by the tumor to stop immune cells from attacking the cancer cells, thereby releasing a brake on anti-cancer immunity.
During the first 6 months, the Team reports that:
- Phase 1 of the CRC clinical trial, which has determined safety, efficacy, and appropriate dosing of combined SGI-110 + irinotecan in patients is near completion, and should be concluded by September 2015.
- They have been preparing the necessary materials for the AML clinical trial.
- They are working on methods for a clinical trial of SGI-110 with pembrolizumab in patients with AML/MDS.
During the next 6 months, the Team will complete their Phase 1 clinical trial in CRC patients and begin working on the Phase 2 portion of this clinical trial. They will obtain the necessary approvals to start the AML clinical trial as well as develop the methods and materials needed for the third clinical trial.
The Team continues to progress toward their overarching goal of bringing the most promising laboratory concepts into clinical trials for patients with various types of cancer. Two lung cancer clinical trials continuing from the original SU2C Epigenetics Dream Team as follows:
- Legacy Lung Cancer Project. The purpose of this trial is to test a combination of epigenetic agents to see whether they sensitize lung cancer patients to immune checkpoint therapy. The trial is enrolling patients at a steady pace.
- NIH-NCI-Cancer Therapy Evaluation Program (CTEP). The purpose of this trial is to test a combination of epigenetic agents to see whether they sensitize lung cancer patients to subsequent chemotherapy. The protocol for this trial has been changed to include lung cancer patients that have failed with immune checkpoint therapy and rapid accrual is not anticipated.
Updates on the three main projects of the VARI-SU2C Epigenetics Dream Team include:
- CRC Project. As of January 2016, this Phase 2 trial will begin enrolling patients.
- AML Project. The clinical trial has been delayed due to lack of industry support for the PARPi study drug. Preclinical studies are underway with alternative PARP inhibitors.
- MDS Project. The regulatory paperwork for this clinical trial has been submitted.
Over the next 6 months, the Team will continue to enroll patients in the 3 open clinical trials and hopes that the delay in the AML will be resolved. They expect to open the MDS trial in the next 6 months.
- The Team continues progress in all 4 projects and have begun pursuing two new, preclinical projects.
- The first trial of the Legacy Lung Cancer project is steadily accruing patients. The second trial, sponsored by CTEP, has been closed due to slow patient accrual.
- The CRC project is steadily enrolling patients at three sites.
- The AML project is anticipated to start in August 2016 with regulatory approvals underway.
- The MDS project is anticipated to start in August 2016 with regulatory approvals underway.
- The fifth project was introduced recently and is referred to as the EZH2i SCLC project. This project is in the preclinical phase testing the use of an inhibitor of the Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2i) in combination with chemotherapy in small cell lung cancer cell lines and mouse models. EZH2 is frequently over-expressed in a wide variety of cancer types.
- The sixth new project is also in the preclinical phase and is entitled EVITA (Epigenetics, Vitamin C, and Abnormal Hematopoesis). In this project, the Team will evaluate whether supplementation with Vitamin C (to restore normal Vitamin C levels) will improve the effects of epigenetic therapy in patients with MDS/AML.