Research Focus

 

Focus Area 1: Integrative Genomics of Cancer 

Since discovery of TMPRSS2-ETS gene fusions in prostate cancer1,2, the Chinnaiyan Lab has pursued a better understanding of the mechanisms by which these gene fusions are involved in prostate cancer pathogenesis. Additionally, due to its specific expression in prostate cancer, the Chinnaiyan Lab has worked to develop non-invasive urinary biomarker assays incorporating the TMPRSS2-ERG gene fusion for early detection of prostate cancer. The original version of this assay, called MyProstateScore (MPS), measured urinary transcript levels of TMPRSS2-ERG and PCA3, a prostate-specific long non-coding RNA (lncRNA), in addition to serum prostate-specific antigen (PSA) levels3. More recent efforts have led to the development of MPS2.0, a clinically available, 18-gene multiplex panel that outperforms PSA and other biomarker tests in detecting high-grade prostate cancer4. MPS2 is now available as a convenient, at-home urine test5. In ongoing research, the Chinnaiyan Lab is pioneering the development of new sequencing-based urinary assays for prostate cancer detection.

The Chinnaiyan Lab continues to identify new genetic drivers of cancer through its Mi-Oncoseq clinical sequencing program for advanced cancer patients. Key recent studies emanating from the Mi-Oncoseq program include characterization of CDK12-mutant metastatic castration-resistant prostate cancer (mCRPC)6, identification of FOXA1 alterations in prostate cancer7, an integrative genomic analysis of relapsed refractory multiple myeloma8, and delineation of the circular RNA (circRNA) landscape in cancer9. Further, a recent study analyzed the clinical benefit afforded by next-generation sequencing (NGS) through the Mi-Oncoseq program10. Results from this study demonstrate the clinical value of NGS, particularly in patients with rare cancers or those of unknown primary origin. Ongoing research is leveraging long-read sequencing technology to comprehensively map genetic alterations in advanced cancers.

 

Focus Area 2: Functional Characterization and Targeting of Oncogenic Transcription Factor Neo-Enhanceosomes

Aberrant transcription factor expression or activity can drive development and progression of cancers. Transcription factors work in complex with coactivators and epigenetic regulators to create active chromatin environments at enhancer sites to hyper-activate expression of oncogenic gene programs. The Chinnaiyan Lab is pursuing several lines of investigation centered around better understanding the function of components of these “neo-enhanceosome” complexes and how they may be therapeutically targeted. One recent study characterized alterations that occur in the FOXA1 pioneer transcription factor, which are found in 35% of all prostate cancers, and showed that the mutations can be grouped into three different structural classes7. A follow-up study characterized FOXA1 mutations in genetically engineered mouse models and demonstrated that class 1 mutations drive androgen dependent-prostate cancers by amplifying androgen receptor (AR) signaling and mTORC1/2 pathways11. In contrast, class 2 FOXA1 mutations reprogram luminal cells into a progenitor-like state to support survival under castrate androgen levels. Projects centered around development of small molecule inhibitors and degraders that can directly target the oncogenic transcription factors FOXA1, MYC, and ERG are being pursued.

Further research has explored targeting epigenetic regulators that are required for neo-enhanceosome activity as an indirect strategy to block oncogenic transcription factor signaling. The Chinnaiyan Lab has shown that proteolysis targeting chimera (PROTAC) degraders of the SMARCA2 and SMARCA4 ATPase subunits of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex prevent transcription factor access at enhancer sites12. SMARCA2/4 PROTACs have anti-tumor efficacy in preclinical models of prostate cancer, small cell lung cancer, and multiple myeloma12,13. Importantly, an orally bioavailable candidate has been developed that shows favorable safety profiles in preclinical models14, and the team is working towards translation of a mSWI/SNF ATPase degrader to the clinic. Another recent study in the lab examined the histone lysine acetyltransferases p300 and CBP as key components driving neo-enhanceosome activity in prostate cancer, with an orally bioavailable PROTAC degrader of p300 and CBP showing anti-tumor activity in preclinical models15,16. NSD2, a histone H3 lysine 36 mono- and di-methyltransferase, is also being pursued as a key mediator driving AR activity at neo-enhanceosomes specific to prostate cancer versus normal cells17.

Finally, several studies are investigating CDK12, a transcriptional kinase that phosphorylates serine residues within the C-terminal domain of RNA Pol II essential for transcriptional elongation. As mentioned above, biallelic loss of CDK12 is enriched in mCRPC4. Recent studies in the Chinnaiyan Lab have shown that CDK12 is a bona fide tumor suppressor gene through generation of prostate-specific Cdk12 knockout mice18. Importantly, Cdk12 inactivation sensitizes prostate tumors to small molecule inhibitors targeting CDK12 and its paralog kinase, CDK1318. Further studies showed that degradation of both CDK12 and CDK13 with an orally bioavailable PROTAC degrader led to a synthetic lethal relationship with AKT inhibitors19. A recent study confirmed Cdk12 as a tumor suppressor gene in tubo-ovarian high-grade serous carcinoma (HGSC)20. Mechanistically, in CDK12-mutant cancers, inactivation of CDK12/CDK13 induces cytosolic nucleic acid release and activates the STING pathway, which drives T cell infiltration into the tumor microenvironment and promotes synergy with anti–PD-1 therapies21. Ongoing projects are aimed at development and translation of CDK13-selective inhibitors.  

 

Focus Area 3: Characterization of PIKfyve as a Therapeutic Target in Cancer 

PIKfyve is a class III lipid kinase crucial for lysosomal functioning that is being explored by the Chinnaiyan Lab as a promising therapeutic target in several types of cancer. Interest in PIKfyve began after a multi-tyrosine kinase inhibitor screen identified the clinical compound ESK981 as a potent inhibitor of prostate cancer cell growth22. Functional assays identified PIKfyve as a target of ESK981 and showed that PIKfyve inhibition decreases autophagic flux in prostate cancer cells. PIKfyve inhibition led to potentiation of immune checkpoint blockade responses in preclinical models of prostate cancer. Follow-up studies found that PIKfyve suppresses anti-cancer immune responses by decreasing dendritic cell function23 and attenuating surface expression of major histocompatibility complex class I (MHC-I) in cancer cells24.   

PIKfyve is also being pursued as a promising target in pancreatic ductal adenocarcinoma (PDAC), a cancer type with a poor prognosis and limited treatment options. The Chinnaiyan Lab recently found that PIKfyve is expressed at higher levels in PDAC compared to normal cells in both human and mouse samples25. This study further employed genetically engineered mouse models of Pikfyve knockout to demonstrate that PIKfyve is essential for PDAC progression. Interestingly, pharmacological or genetic inhibition of PIKfyve upregulates de novo lipid synthesis, which induces a synthetic lethal relationship with KRAS-MAPK-directed therapies for PDAC.

While ESK981 and another PIKfyve inhibitor, apilimod, are useful tools to probe the biology and function of this pathway, a PIKfyve-specific inhibitor with oral bioavailability and other favorable clinical properties is desirable for translation to patients. The Chinnaiyan Lab is actively working on developing novel PIKfyve inhibitors or degraders26 with the goal of advancing a compound to the clinic.

 

See Full Bibliography

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References

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  9. Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, Wu YM, Dhanasekaran SM, Engelke CG, Cao X, Robinson DR, Nesvizhskii AI, Chinnaiyan AM. The Landscape of Circular RNA in Cancer. Cell. 2019;176(4):869-81 e13. PMID: 30735636; PMCID: PMC6601354.
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  20. Tien JC, Zhai Y, Wu R, Zhang Y, Chang Y, Cheng Y, Todd AJ, Wheeler CE, Li S, Mannan R, Cheng C, Magnuson B, Cruz G, Cao Y, Mahapatra S, Stolfi C, Cao X, Su F, Wang R, Yang J, Zhou L, Qiao Y, Xiao L, Cieslik M, Wang X, Wang Z, Chou J, Fearon ER, Ding K, Cho KR, Chinnaiyan AM. Defining CDK12 as a tumor suppressor and therapeutic target in mouse models of tubo-ovarian high-grade serous carcinoma. Proc Natl Acad Sci U S A. 2025;122(24):e2426909122. PMID: 40504161; PMCID: PMC12184368.
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  24. Bao Y, Qiao Y, Choi JE, Zhang Y, Mannan R, Cheng C, He T, Zheng Y, Yu J, Gondal M, Cruz G, Grove S, Cao X, Su F, Wang R, Chang Y, Kryczek I, Cieslik M, Green MD, Zou W, Chinnaiyan AM. Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy. Proc Natl Acad Sci U S A. 2023;120(49):e2314416120. PMID: 38011559; PMCID: PMC10710078.
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Research Focus
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