Exploring novel therapeutic strategies for combinatory therapy to treat renal clear cell carcinomas

项目Summary-Abstract

Project Summary-Abstract Renal cell carcinomas (RCC) are among the 10 most common cancer types in man (6th) and woman (8th) worldwide. Most RCC are clear cell carcinomas (>80%) that represent an atypical cancer type in many ways including the intrinsic resistance to many chemotherapeutics, sensitivity to anti-neoangiogenesis, and sensitivity to immune checkpoint inhibitors but with very low mutational burden. The treatment landscape of RCC has been changing rapidly in the last couple of years but still with very low complete response rate even with the most updated treatment regimens. Those “atypical” features of RCC prompted us to perform a comprehensive single cell RNA sequencing for human ccRCCs and paired bloods. We found that tumor induced Tregs are highly suppressive to effector T cells and could be the major immune cells conferring the immune suppressive tumor microenvironment (TME). These TI-Tregs have the typical signs of cellular senescence, including the expression of p16, p21, BCL-XL, senescence-associated secretory phenotype (SASP), and the activation of β-galactosidase (β-Gal). The group recently reported the development of the first-in-class BCL-XL degraders, i.e. the Proteolysis Targeting Chimeras (PROTACs, referred to as BCL-XL-Ps). DT2216, a lead BCL-XL-P, targets BCL-XL to the von Hippel-Lindau (VHL) E3 ligase; and PZ15227 targets BCL-XL to the cereblon (CRBN) E3 ligase for ubiquitination and subsequent degradation by the proteasome. We have found these two senolytics are very effective in eliminating TI-Tregs and activate anti-tumor immunity in our recent publication. Based on these novel findings, we hypothesize that aging- and cancer-associated cellular senescence – including senescence from immune cells – is critical in RCC pathogenesis and cancer progression via modulating the tumor immune microenvironment. Understanding these fundamental questions is important for rational design of therapeutic regimens towards to RCC that remains an urgent and unmet clinical need. Specific Aim 1 is to establish the mechanistic connection between cellular senescence – in particular Treg senescence – and RCC with special focus on the modulation of tumor immune microenvironment. Aim 2 is to determine the therapeutic efficacy of senolytic depletion of TI-Tregs and common therapeutics in RCC. The team has expertise in clinical renal cancer, cellular senescence, in particular the senolytic drug development and senescence tracing, cancer models and cancer immunology. We will establish the role of tumor infiltrating Tregs in immune modulation within the tumor microenvironment and determine the efficacy of targeting senescent Tregs in RCC cancer therapy, by combining with anti-neoangiogenesis drugs or immune checkpoint inhibitors.