The recent FDA approvals of Lutathera and Pluvicto, multiple billion dollar acquisitions of radiopharmaceutical companies (e.g. Rayzebio, Point Biopharma, Fusion Pharmaceuticals), and the swell of promising drug candidates in development, fully underscore the surging enthusiasm for targeted radiotherapy as a cancer treatment strategy. With this renaissance comes the urgent need to identify cancer specific proteins to avoid the toxicities associated with radiopharmaceuticals whose targets are expressed in normal and tumor tissues.
In collaboration with the Wells lab at UCSF (https://wellslab.ucsf.edu/), we are addressing thsi unmet need by applying proteomics to identify proteins on the cancer cell surface that are strongly induced by undruggable oncogenes (e.g. RAS, transcription factors). Because we are focusing on the surface-ome, antibodies can be rapidly evolved through phage display to bind highly upregulated proteins, and of course functionalized with radioisotopes for imaging or endoradiotherapy.
Following on a recent manuscript describing how mutant KRAS remodels the cancer cell surface-ome, we have shown for the first time that antibodies targeting the ectodomain of CUB domain containing protein 1 can be labeled with radioisotopes to visualize (e.g. Zr-89) and treat (Lu-177, Ac-225) RAS driven cancers. CDCP1 is broadly upregulated in cancer, so the technologies and proof of concept treatment data may have therapeutic applications beyond RAS driven cancers.
Moving forward, we are continuing to collaborate closely with the Wells lab to develop several new proteomics data sets to identify cell surface proteins uprregulated by other "undruggable" or poorly druggable oncogenic drivers of cancer. For example, we recently disclosed how mTORC1 activity remodels the cell surface-ome, which may lead to more ablative therapeutic strategies compared to treatment with cytostatic rapalogues.
Relevant publications:
- Martinko AJ, Truillet C, Julien O, Diaz JE, Horlbeck MA, Whiteley G, Blonder J, Weissman JS, Bandyopadhyay S, Evans MJ, Wells JA. Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins. Elife. 2018 01 23; 7. PMID: 29359686.
- Moroz A, Wang YH, Sharib JM, Wei J, Zhao N, Huang Y, Chen Z, Martinko AJ, Zhou J, Lim SA, Zhang LH, Seo Y, Carlin S, Leung KK, Collisson EA, Kirkwood KS, Wells JA, Evans MJ. Theranostic targeting of CUB domain containing protein 1 (CDCP1) in pancreatic cancer. Clin Cancer Res. 2020 Apr 27. PMID: 32341034.
- Wei J, Leung K, Truillet C, Ruggero D, Wells JA, Evans MJ. Profiling the Surfaceome Identifies Therapeutic Targets for Cells with Hyperactive mTORC1 Signaling. Mol Cell Proteomics. 2020 02; 19(2):294-307. PMID: 31792071.
- Theranostic Targeting of CUB Domain-Containing Protein 1 (CDCP1) in Multiple Subtypes of Bladder Cancer. Clin Cancer Res. 2023 04 03; 29(7):1232-1242.Chopra S, Trepka K, Sakhamuri S, Carretero-González A, Zhu J, Egusa E, Zhou J, Leung K, Zhao N, Hooshdaran N, Feng FY, Wells JA, Chou J, Evans MJ. PMID: 36648492; PMCID: PMC10073270.
- CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease. Clin Cancer Res. 2022 07 15; 28(14):3066-3075.Zhao N, Chopra S, Trepka K, Wang YH, Sakhamuri S, Hooshdaran N, Kim H, Zhou J, Lim SA, Leung KK, Egusa EA, Zhu J, Zhang L, Foye A, Sriram R, Chan E, Seo Y, Feng FY, Small EJ, Chou J, Wells JA, Aggarwal R, Evans MJ. PMID: 35604681; PMCID: PMC9288514.