Our First Focus:
Prostate cancer (PCa) is one of the most commonly diagnosed cancers in the world and one of the leading causes of cancer-related deaths worldwide (1, 2). Although most men diagnosed with prostate cancer do not die from it (3), the major cause of death from prostate cancer is metastasis to the bone because PCa cells show a tropism to the bone (4). An autopsy study revealed that 90% of men who had died with metastases of PCa were diagnosed with bone metastases (5). The current standard-of-care for primary or metastatic, castration-resistant prostate cancer is docetaxel. However, docetaxel has moderate and common side effects, including hypersensitivity reactions (28% of patients) that could lead to cardiorespiratory distress, angioedema, anaphylaxis, and urticaria (6, 7). In addition, 10% of patients have long term neurotoxicity, experiencing debilitating peripheral sensory and motor neuropathies (6). In PCa patients with bone metastases, docetaxel is not very effective treatment due to systemic toxicity, resulting of 33% in the 5-year survival rate (8). Thus, there is an urgent need for new therapeutic PCa options that include effective treatment of PCa in the bone that can limit the toxicity of the current standard-of-care.
Our first focus is on developing novel prostate-specific membrane antigen (PSMA)-targeted multivalent taxane conjugates (taxane-MDCs) that selectively target prostate cancer cells in both bone metastases and primary tumors, minimizing toxicity. We aim to achieve this using our proprietary patented multivalent synthetic chemistry. Our approach involves preparing multivalent taxane drug-conjugates by attaching a paclitaxel/docetaxel payload to multiple iterations of water-soluble and targeting molecules. This design offers several benefits:
Increased water solubility improves distribution into the bone and allows for increased dosing.
Enhanced selectivity improves uptake by prostate cancer cells and reduces non-specific uptake by other cells.
By releasing the free drug as effectively as chemotherapy, our novel MDCs deliver a triple attack against prostate cancer, leading to improved efficacy and reduced toxicity.
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References:
1. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Pineros M, Znaor A, Bray F. 2021. Cancer statistics for the year 2020: An overview. Int J Cancer
2. Grus T, Lahnif H, Bausbacher N, Miederer M, Rösch F. 2022. DOTA Conjugate of Bisphosphonate and PSMA-Inhibitor: A Promising Combination for Therapy of Prostate Cancer Related Bone Metastases. Frontiers in Nuclear Medicine 2
3. Immisch L, Papafotiou G, Popp O, Mertins P, Blankenstein T, Willimsky G. 2023. Response to: Correspondence on 'H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2+ patients with diffuse midline glioma' by Chheda et al. J Immunother Cancer 11
4. Baldessari C, Pipitone S, Molinaro E, Cerma K, Fanelli M, Nasso C, Oltrecolli M, Pirola M, D'Agostino E, Pugliese G, Cerri S, Vitale MG, Madeo B, Dominici M, Sabbatini R. 2023. Bone Metastases and Health in Prostate Cancer: From Pathophysiology to Clinical Implications. Cancers (Basel) 15
5. Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, Gasser TC, Mihatsch MJ. 2000. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 31: 578-83
6. Ho MY, Mackey JR. 2014. Presentation and management of docetaxel-related adverse effects in patients with breast cancer. Cancer Manag Res 6: 253-9
7. Schrijvers D, Wanders J, Dirix L, Prove A, Vonck I, van Oosterom A, Kaye S. 1993. Coping with toxicities of docetaxel (Taxotere). Ann Oncol 4: 610-1
8. Kingsley LA, Fournier PG, Chirgwin JM, Guise TA. 2007. Molecular biology of bone metastasis. Mol Cancer Ther 6: 2609-17