The Fight Colorectal Cancer-AACR Fellowship, in memory of Lisa Dubow, is a one-year grant to support the salary and benefits of the fellow. A partial amount of funds, up to 25 percent of the total grant, may be designated for direct research expenses. Research projects are restricted to translational or clinical cancer research that has an ultimate goal of developing or improving therapeutic interventions for patients with metastatic colorectal cancer.
2011 GRANTEE
Jon H. Chung, Ph.D.Postdoctoral Fellow, Johns Hopkins University, Baltimore, MD
Hedgehog Pathway Targeted Therapeutics for Metastatic Colorectal Cancer
"Despite advances in colorectal cancer treatment, the prognosis for patients with metastatic disease remains poor. In recent years much progress has been made in our basic understanding of the signaling pathways that underpin the transition of colorectal cancer from localized to metastatic disease. Several developmental signaling pathways are activated in association with colorectal cancer metastasis; these pathways present new opportunities to develop anti-metastatic therapies.
Constitutive signaling by the Wnt/APC pathway has long been understood to be a major driver of colorectal cancer. The Hedgehog signaling pathway has recently emerged as another key player in colorectal carcinogenesis and this pathway is progressively activated during metastasis. The switch to Hedgehog pathway activation that occurs as tumors metastasize presents an opportunity for developing therapies for metastatic colorectal cancer. My project will focus on targeting the Hedgehog pathway.
The current paradigm for treating cancers with activated Hedgehog signaling involves the use of drugs that directly inhibit canonical pathway components, such as Smoothened. However, disappointing results in clinical trials for metastatic colorectal cancer and the propensity of cancers to become resistant to Hedgehog pathway inhibitors suggest that alternative approaches are also needed.
The Hedgehog pathway also crosstalks with non-canonical pathways, including the Wnt and DNA damage signal transduction pathways. In contrast to current strategies that directly target canonical Hedgehog signaling, I will use two alternative approaches that will exploit Hedgehog pathway crosstalk with non-canonical pathways. First, I will examine crosstalk between the Hedgehog and Wnt pathways and screen for drugs that simultaneously inhibit Hedgehog and Wnt signaling, two critical and interacting pathways that drive colorectal carcinogenesis. Second, I will identify DNA damage pathway components that can be targeted to cause synthetic lethal interactions in the context of activated Hedgehog signaling.
I am excited about the opportunity to conduct this project and hope this research will contribute to the discovery of potential new therapies for patients with metastatic colorectal cancer. It is an honor to be awarded the Fight Colorectal Cancer-AACR Fellowship in memory of Lisa Dubow. The generous support provided by this award will allow me to advance this project and will help develop my career as a cancer researcher. I am also very grateful to my advisor Dr. Fred Bunz who has always encouraged me to pursue my ideas and supported me throughout my postdoctoral training."
Top of Page
2010 GRANTEE
AACR-Colorectal Cancer Coalition Fellows Grant, in memory of Lisa Dubow
Rona D. Yaeger, M.D.Clinical Research Fellow, Memorial Sloan-Kettering Cancer Center, New York, NY
A Translational Study of Inhibiting AKT to Treat Colorectal Cancer
"New approaches for colorectal cancer patients whose disease is refractory to existing therapies are needed. My research evaluates the role of AKT activation in colorectal cancer and the possibility of selectively targeting AKT to control metastatic colorectal cancer. AKT is a key signaling molecule that integrates mitogenic and nutrient inputs to promote cell growth and survival and, therefore, represents an appealing clinical target. AKT functions as a node within an intersecting biochemical network that includes the RAS-MAPK (Mitogen Activated Protein Kinase) and PI3K (phosphatidylinositol 3-kinase) signaling pathways. These pathways are frequently activated in colorectal cancer; mutations in KRAS occur in approximately 30-50 percent of metastatic colorectal cancer cases and mutations in all components of the PI3K signaling pathway have been found in colorectal cancer, occurring in about 40 percent of colorectal tumors. We will conduct a clinical trial that looks at the therapeutic benefit of a selective AKT inhibitor in patients with KRAS-wild-type metastatic colorectal cancer. This Phase II study will evaluate overall response rate, progression-free survival, overall survival and adverse events for treatment with the selective AKT inhibitor MK-2206 (Merck) in patients with KRAS-wild-type colorectal cancer whose tumors have progressed through standard chemotherapy regiments. In colorectal tumors with activated KRAS, clinical experience with epidermal growth factor receptor antagonists and preclinical work with MAPK inhibitors suggest that biologic agents targeting mitogen signaling pathways may be less effective. However, PI3K/AKT signaling is activated by KRAS and appears necessary for KRAS-induced tumorigenesis. We will conduct preclinical experiments to determine the dependence of KRAS-mutated tumors on AKT signaling and to define the effects of AKT inhibition on cell signaling, translation and growth in sensitive and resistant KRAS-mutated colorectal tumors. Using preclinical models of KRAS-mutated colorectal tumors, we will try to identify determinants of sensitivity to AKT inhibition. It is our hope that by identifying determinants of AKT dependence of KRAS-mutated colorectal tumors, our work will help guide rational selection of patients for clinical trials with targeted agents and expand treatment options for patients with KRAS-mutated colorectal tumors.
"It is a great honor to be awarded the AACR-Colorectal Cancer Coalition Fellows Grant, in memory of Lisa Dubow. I am lucky to have the guidance of two excellent mentors. I perform experiments in the laboratory of Dr. Neal Rosen and conduct the clinical trial under the direction of Dr. Leonard Saltz. Drs. Rosen and Saltz have been incredible role models and I am grateful to them for supporting and challenging me."
Top of Page