Satya Narayan, PhD

Targeting DNA repair and replication pathways for therapy of colorectal cancer: The traditional view of cancer development suggests that all neoplastic cells within a tumor contain tumorogenic growth capacity. However, it is evident from existing literature that only a small subset of bulk colon cancer cells (CRC-Cs) are able to initiate tumor growth. This sub-set of cancer-initiating cells is identified as colorectal cancer stem cells (CRC-SCs). CRC-SCs possess: (i) capacity for self-renewal, (ii) potential for multi-lineage differentiation, (iii) ability to drive continued expansion and survive into adverse tissue micro-environment, and (iv) ability to invade and metastasize. Elimination of the self-renewal capacity is required to overcome clinical relapses and ultimate death from CRC progression. Current standard therapy for CRC is based upon the DNA-damaging drug, oxaliplatin (OXR) and nucleotide analogue, 5-fluorouracil (5-FU). Although very common, metastatic colorectal cancer (CRC) remains one of the most challenging cancers to treat due to inherent drug resistance. This project will examine whether DNA repair and replication pathways can be targeted to enhance the cytotoxicity of CRC therapies. The overall goal of this pre-clinical study is to advance not only the understanding of DNA repair after standard CRC chemotherapy, but also to strategically develop novel small molecules that will be used to improve therapeutic outcomes for CRC patients. Our studies focus on both bulk and cancer stem cell populations as a target for therapeutic intervention of CRC. Our studies are also directed toward developing novel structure-based small molecule inhibitors for breast and pancreatic cancers and glioblastoma.

Mechanisms of cigarette smoke-induced breast and lung carcinogenesis: Many epidemiological studies suggest a strong link between smoking, the number of cigarettes smoked, and the incidence of breast cancer in women. However, other epidemiologic studies conflict with the association between cigarette smoking and breast cancer risk. In our studies by using an in vitro cell culture and in vivo animal models, we have shown that cigarette smoke condensate (CSC), a surrogate of cigarette smoke causes transformation of normal breast epithelial cells in the in vitro and in vivo studies. We have shown that adenomatous polyposis coli (APC) is a multifunctional protein having diverse cellular functions including cell migration, cell-cell adhesion, cell cycle control, chromosomal segregation and apoptosis plays a critical and new role in CSC-induced transformation of normal breast epithelial cells. We have examined the molecular mechanisms by which CSC and its major component, Benzo[α]pyrene, enhances APC-mediated accumulation of abasic DNA lesions, which is cytotoxic and mutagenic in nature, leading to enhanced neoplastic transformation of normal breast epithelial cells in an orthotopic xenograft model. Our current focus is to determine the molecular mechanisms by which DNA base excision repair might play a role in cigarette smoke-induced lung carcinogenesis.

Role of APC in DNA repair: Our recent studies suggest that the product of the adenomatous polyposis coli (APC) gene can modulate base excision repair (BER) pathway through an interaction with DNA polymerase β (Pol-β) and flap endonuclease 1 (Fen-1). Taken together with our finding that the transcription of APC is enhanced by alkylating agents, our results suggest that APC modulation of BER activity may play an important role in carcinogenesis and chemotherapy by determining whether cells with DNA damage survive or undergo apoptosis. These findings can have implications for the development of more effective strategies for chemoprevention, prognosis, and chemotherapy of colorectal as well as other types of solid tumors.