Many cell types require integrin-mediated adhesion to the extracellular matrix for survival. However, most solid tumors are capable of survival and growth independent of integrin engagement (called “anchorage independent growth”). Some of these cancers exhibit synergy between adhesion and DNA damage pathways such that poorly adherent/integrin independent cells are resistant to radiation and DNA-damaging chemotherapy. These data suggest a causal relationship between progression to anchorage independent growth and acquisition of resistance to DNA-damaging therapies. Importantly, published data also show that this process can be reversible: exogenous activation of integrin signaling can specifically re-sensitize cancer cells to these widely used DNA- damaging modalities. These observations support the hypothesis that loss of integrin signaling could be an important factor in cancer responses to therapy, and that integrin reagents may be effective adjuncts to therapy.
Based on these results, the current projects have three interrelated goals. First, we will test these hypotheses in order to establish a stronger link to human disease. Second, these studies will help develop diagnostics to identify the small fraction of patients, who are most likely to benefit from chemotherapy. Third, we will develop integrin reagents that could be used in patients to enhance responses to chemotherapy and radiation.
Our ongoing work focuses on testing the importance of integrin signaling in therapeutic responses of melanoma and prostate cancer, which will determine whether there is a gene expression signature that correlates with adhesion-dependence of therapy responses. We are also developing/ testing peptide-based reagents that can stimulate integrin signaling which can increase sensitivity to DNA damage. We plan to extend these studies to identify how loss of adhesion mediated signaling contributes to tumor progression and how radiation could modify theseprocess. Furthermore we will utilize exome sequencing to identify correlations between adhesion dependence of therapy sensitivity and mutations implicated in cancer progression. These studies will provide a basis for further mechanistic studies and also have the potential to lead to development of diagnostics to identify the subset of patients that would benefit from integrin adjuvant therapy.
Kumari Andarawewa, DVM, MSS, PHD
Assistant Professor of Radiation Oncology
University of Virginia School of Medicine
PO Box 800383