Scientific Objective and Rationale: Cancer is a complex disease that can originate in multiple different cell types of the organism and is often fatal in humans. One of the reasons for our struggle to combat cancer is its sheer diversity, which is making it difficult to pinpoint a specific molecule on which the propagation of cancer cells depends, a molecule that could be targeted by a drug to selectively eradicate cancerous cells but leave the normal tissue intact. Recent studies have identified a very unique group of molecules called "chromatin regulators," also known as "epigenetic regulators," that are frequently compromised in various types of cancer. Chromatin regulators control the state of chromatin (i.e., DNA and the associated proteins), its compaction level and thus the activity of genes. More broadly, chromatin regulators control cell fate decisions through a fine balance between cell differentiation and cell proliferation. Cancer arises when this balance tilts in favor of proliferation. Traditional approaches in cancer research are based on comparisons between normal vs. cancerous, or control vs. drug-treated to figure out what goes awry when cancer arises. However, the complexity of the disease often obscures the lesions that give rise to cancer, and so more rigorous approaches are needed to identify the primary molecular event that drives the propagation of cancer cells.
Here I propose to compare the development of cancer to a process used in stem cell technology, where mature (differentiated) cells are reprogrammed in tissue culture dish to their immature (de-differentiated) origin to become "induced pluripotent stem cells" (iPSCs). Reprogramming to iPSCs recapitulates the key features of cancerous cell transformation. For example, in both instances a slowly dividing, normal differentiated cell with a specialized function converts into an immortal and often rapidly dividing stem-like cell that acquires different functions. Similarities are also apparent on the molecular level where several chromatin regulators important during carcinogenesis play key roles in cellular reprogramming to turn a compacted chromatin of differentiated cells into the "open" chromatin of stem cells. Therefore, by searching for common features between these systems, my strategy is geared towards identification of chromatin regulators that are generally important for cancer formation. Blocking the activities of these chromatin regulators with low-molecular-weight inhibitors has the potential for selective treatment of cancers of different etiologies. More specifically, I propose to test the epigenetic enhancers of reprogramming in Acute Myeloid Leukemia (AML) that can be studied in mouse models of the human disease.
Career Goals in Cancer Research: My long-term career goal is to make milestone discoveries that will improve cancer therapy. This will only be possible if I become an independent cancer researcher. My scientific background and the proposed work will help me achieve this by providing me with the necessary resources and guidance by the experts in the fields of cancer and stem cell biology. My proposal to systematically investigate epigenetic parallels between carcinogenesis and reprogramming to pluripotency carries high potential for identification of direct drug targets, as it is based on a powerful screen that explores the general vulnerabilities of cancer cells. I envision that stemness acquired during cancer development and stemness generated during cellular reprogramming require a similar mode of chromatin regulation. This constitutes the central paradigm of my proposal, and the line of research that I want to pursue as I continue my career in cancer research as an independent investigator.
Applicability of the Research: Since most if not all types of cancers depend on a rare population of cancerous cells with stem-like properties, the identification of critical chromatin regulators of cell stemness can be expected to have broad implications for cancer therapy. Blocking the activities of these chromatin regulators with low-molecular-weight inhibitors as cancer therapeutics has the potential for selective targeting of cancer stem cells of different etiologies. Put another way, drugs targeting chromatin regulators to be identified in this proposal could be used to treat patients with different types of cancers and at different stages of disease progression. Moreover, since the rare population of cancer stem cells is the primary cell type that is dependent on a particular chromatin regulator for stemness, such drugs can be expected to be selective with few or mild side effects. In addition, acute (short-lasting) treatment of patients with such drugs would likely suffice, as cancer stem cells would rapidly lose their drive to proliferate and instead differentiate. Finally, since this type of therapy is non-invasive and easily tolerated by the organism, it would be applicable to the U.S. veterans, active duty service members and their immediate family members. I expect to conclude the identification and validation of drug targets within the proposed 3 years, and the process of drug design and preclinical testing may take as much time before the first cancer patients are treated during the clinical phase of drug testing. However, this still presents a time saving of several decades compared to the traditional approaches in cancer research, let alone screening of large chemical libraries to identify active compounds.