TARGETING MYC ONCOGENE TO OVERCOME CHEMORESISTANCE IN MUSCLE INVASIVE BLADDER CANCER

The basal subtype muscle invasive bladder cancer (MIBC) has a short survival rate before the onset of chemoresistance and associated toxicity. Thus, there is a clinical need to balance chemotherapeutic toxicity with treatments to eradicate bladder cancer (BCa). Transcription factors, which drive gene signatures associated with normal organ development as well as aggressive cancer phenotypes, may be the key determinants of progression and therapeutic response. In the normal mouse genitourinary tract, p63-positive cells are necessary for the development of bladder and are capable of forming all cell lineages. This suggests that p63 may serve an equally important role in the basal MIBC etiologies. While human BCa cell lines exist, they may not reflect the complexity of human BCa and adaptation to treatments due to divergent evolution during the long-term in-vitro culture. To overcome this challenge, a novel mouse derived allograft (MDA) of MIBC resistant to cisplatin, a chemotherapy drug, was developed using OH-BBN (0.1%, N-Butyl-N-4-hydroxybutyl nitrosamine), a carcinogen. OH-BBN induced BCa was confirmed to represent basal subtype MIBC, which overexpresses p63 and MYC. We also adapted a patient derived xenograft (PDX) from MIBC patients who are experiencing chemoresistance by implanting the BCa tumor into mice. The clinical samples have been confirmed to overexpress p63 and MYC. After the MDA was treated with cisplatin CDDP, chemoresistance was observed through tumor volume measurements and immunohistochemistry. Bromodomain and Extra-Terminal (BET) inhibitor, JQ1, and CDDP were tested individually and in combination on the MDA and PDX. The average tumor volumes were compared, and results showed in both models that the effects of the combination treatment was significant (p<0.05). This suggests that the p63 signaling pathway drives MYC signaling to regulate progression and chemoresistance in MIBC. In the future, the combination treatment in an orthotopic mouse model can be investigated.