UBC Theses and Dissertations
Identification of a mechanism of resistance and sub-classification of patients for treatment-decision making in clear-cell renal cell carcinoma D'Costa, Ninadh Malrina
Clear-cell renal cell carcinoma (ccRCC) is a disease with aberrant angiogenic and immunosuppressive features. Metastatic ccRCC patients are treated with targeted therapies based on clinical features: favorable-risk patients with a combination of anti-angiogenic and immunogenic drugs, and intermediate/high-risk patients with immunotherapies. In this doctoral research project, I hypothesized that targeted treatment against factor(s) augmented through drug-resistance development could revert to responding to therapy. I further theorized that ccRCC patients could be sub-classified into treatment groups that might guide therapy decision-making in a personalized manner. Patients treated with anti-angiogenic drugs, e.g. sunitinib, eventually develop resistance and the underlying molecular mechanism is unknown. In Objective 1, I found that an evolutionarily conserved protein, Y-box binding protein 1 (YB-1), and its downstream target, ATP-binding cassette sub-family B member 1 (ABCB-1), were upregulated in acquired sunitinib-resistant in vitro, ex vivo, in vivo and patient samples when compared to sensitive samples. Moreover, co-administration of ABCB-1 inhibitor, elacridar, reverted the sunitinib-resistance in mccRCC tumors. Further anomalies in the expression pattern of ccRCC tumors were explored in Objective 2 and a novel gene signature to sub-classify ccRCC patients was identified. I analyzed the expression profile of 469 ccRCC patients and developed a refined 66-gene signature for improved sub-classification of patients (Angiogenic, Unknown, T-effector). In my 66-gene signature, I identified a novel comprehensive expression profile to distinguish migratory stromal from immune cells. Moreover, “Angiogenic” tumors with higher expression of endothelin-1 (EDN1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) had decreased levels of immune cell gene expression. Previous research showed that EDNRB modulates T-cell infiltration into solid tumors. Augmenting prior research, under Objective 2, the “cross-talk” between tumor vasculature and immune microenvironment (TIME) was explored. Altogether, my thesis identified one possible mechanism of acquired sunitinib-resistance development and potential therapy in mccRCC tumors. The thesis also established that ccRCC tumors have different expression patterns that could be sub-classified into distinct groups. The proposed sub-classification might guide treatment decision-making and, potentially, enable the use of personalized medicine in ccRCC patients increasing treatment response and survival.
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