Research Focus

 

Focus Area 1: Integrative Genomics of Cancer

Since the discovery of TMPRSS2-ETS gene fusions in prostate cancer1, the Chinnaiyan Lab has dedicated effort to understanding 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), measures urinary transcript levels of TMPRSS2-ERG and PCA3, a prostate-specific long non-coding RNA (lncRNA), in addition to serum prostate-specific antigen (PSA) levels2. 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 cancer3. 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)4, identification of FOXA1 alterations in prostate cancer5, an integrative genomics analysis of relapsed refractory multiple myeloma6, and delineation of the circular RNA (circRNA) landscape in cancer7. Further, a recent study analyzed the clinical benefit afforded by next-generation sequencing (NGS) through the Mi-Oncoseq program8. Results from this study demonstrate the clinical value of NGS, particularly in patients with rare cancers or those of unknown primary origin. Ongoing research will leverage 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 the development and progression of different 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 in cancer. 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 classes5. Ongoing studies in the Chinnaiyan Lab are characterizing the FOXA1 mutations in genetically engineered mouse models. Projects centered around the development of small molecule inhibitors and degraders that can directly target the oncogenic transcription factors FOXA1, MYC, and ERG are also 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 sites9. SMARCA2/4 PROTACs have anti-tumor efficacy in preclinical models of prostate cancer, small cell lung cancer, and multiple myeloma9,10. Importantly, an orally bioavailable candidate has been developed that shows favorable safety profiles in preclinical models11, and the team is working towards translation of a mSWI/SNF ATPase degrader to the clinic. Ongoing studies in the lab are also examining 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 models12,13. NSD2, a histone H3 lysine 36 mono- and di-methyltransferase, is also being pursued as a key mediator driving androgen receptor (AR) activity at neo-enhanceosomes specific to prostate cancer versus normal cells14.

Finally, several studies in the lab 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 a generation of prostate-specific Cdk12 knockout mice15. Importantly, Cdk12 inactivation sensitizes prostate tumors to small molecule inhibitors targeting CDK12 and its paralog kinase, CDK13. Ongoing projects are aimed at the 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 growth16. 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 function17 and attenuating surface expression of major histocompatibility complex class I (MHC-I) in cancer cells18.   

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 samples19. 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 degraders20 with the goal of advancing a compound to the clinic.

 

See Full Bibliography

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References

  1. Tomlins, S.A., Rhodes, D.R., Perner, S., Dhanasekaran, S.M., Mehra, R., Sun, X.-W., Varambally, S., Cao, X., Tchinda, J., Kuefer, R., et al. (2005). Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648.
  2. Tomlins, S.A., Aubin, S.M.J., Siddiqui, J., Lonigro, R.J., Sefton-Miller, L., Miick, S., Williamsen, S., Hodge, P., Meinke, J., Blase, A., et al. (2011). Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci. Transl. Med. 3, 94ra72.
  3. Tosoian, J.J., Zhang, Y., Xiao, L., Xie, C., Samora, N.L., Niknafs, Y.S., Chopra, Z., Siddiqui, J., Zheng, H., Herron, G., et al. (2024). Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer. JAMA Oncol. 10.1001/jamaoncol.2024.0455.
  4. Wu, Y.-M., Cieślik, M., Lonigro, R.J., Vats, P., Reimers, M.A., Cao, X., Ning, Y., Wang, L., Kunju, L.P., de Sarkar, N., et al. (2018). Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 173, 1770–1782.e14.
  5. Parolia, A., Cieslik, M., Chu, S.-C., Xiao, L., Ouchi, T., Zhang, Y., Wang, X., Vats, P., Cao, X., Pitchiaya, S., et al. (2019). Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. Nature 571, 413–418.
  6. Vo, J.N., Wu, Y.-M., Mishler, J., Hall, S., Mannan, R., Wang, L., Ning, Y., Zhou, J., Hopkins, A.C., Estill, J.C., et al. (2022). The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma. Nat. Commun. 13, 3750.
  7. Vo, J.N., Cieslik, M., Zhang, Y., Shukla, S., Xiao, L., Zhang, Y., Wu, Y.-M., Dhanasekaran, S.M., Engelke, C.G., Cao, X., et al. (2019). The Landscape of Circular RNA in Cancer. Cell 176, 869–881.e13.
  8. Cobain, E.F., Wu, Y.-M., Vats, P., Chugh, R., Worden, F., Smith, D.C., Schuetze, S.M., Zalupski, M.M., Sahai, V., Alva, A., et al. (2021). Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors. JAMA Oncol 7, 525–533.
  9. Xiao, L., Parolia, A., Qiao, Y., Bawa, P., Eyunni, S., Mannan, R., Carson, S.E., Chang, Y., Wang, X., Zhang, Y., et al. (2022). Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer. Nature 601, 434–439.
  10. He, T., Xiao, L., Qiao, Y., Klingbeil, O., Young, E., Wu, X.S., Mannan, R., Mahapatra, S., Eyunni, S., Tien, J.C.-Y., et al. (2024). Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies. bioRxiv. 10.1101/2024.01.22.576669.
  11. He, T., Cheng, C., Qiao, Y., Cho, H., Young, E., Mannan, R., Mahapatra, S., Miner, S.J., Zheng, Y., Kim, N., et al. (2024). Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer. Proc. Natl. Acad. Sci. U. S. A. 121, e2322563121.
  12. Chen, Z., Wang, M., Wu, D., Zhao, L., Metwally, H., Jiang, W., Wang, Y., Bai, L., McEachern, D., Luo, J., et al. (2024). Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer. J. Med. Chem. 67, 5351–5372.
  13. Luo, J., Chen, Z., Qiao, Y., Ching-Yi Tien, J., Young, E., Mannan, R., Mahapatra, S., He, T., Eyunni, S., Zhang, Y., et al. (2024). p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer. bioRxiv. 10.1101/2024.03.29.587346.
  14. Parolia, A., Eyunni, S., Verma, B.K., Young, E., Liu, L., George, J., Aras, S., Das, C.K., Mannan, R., Rasool, R.U., et al. (2024). NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis. bioRxiv. 10.1101/2024.02.22.581560.
  15. Tien, J.C.-Y., Chang, Y., Zhang, Y., Chou, J., Cheng, Y., Wang, X., Yang, J., Mannan, R., Shah, P., Wang, X.-M., et al. (2024). CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality. bioRxiv. 10.1101/2024.03.20.585990.
  16. Qiao, Y., Choi, J.E., Tien, J.C., Simko, S.A., Rajendiran, T., Vo, J.N., Delekta, A.D., Wang, L., Xiao, L., Hodge, N.B., et al. (2021). Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer. Nat Cancer 2, 978–993.
  17. Choi, J.E., Qiao, Y., Kryczek, I., Yu, J., Gurkan, J., Bao, Y., Gondal, M., Tien, J.C.-Y., Maj, T., Yazdani, S., et al. (2024). PIKfyve controls dendritic cell function and tumor immunity. bioRxiv. 10.1101/2024.02.28.582543.
  18. Bao, Y., Qiao, Y., Choi, J.E., Zhang, Y., Mannan, R., Cheng, C., He, T., Zheng, Y., Yu, J., Gondal, M., et al. (2023). Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 120, e2314416120.
  19. Cheng, C., Hu, J., Mannan, R., Bhattacharyya, R., Rossiter, N.J., Magnuson, B., Wisniewski, J.P., Zheng, Y., Xiao, L., Li, C., et al. (2024). Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer. bioRxiv. 10.1101/2024.03.18.585580.
  20. Li, C., Qiao, Y., Jiang, X., Liu, L., Zheng, Y., Qiu, Y., Cheng, C., Zhou, F., Zhou, Y., Huang, W., et al. (2023). Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve. J. Med. Chem. 66, 12432–12445.

 

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