Enhanced Therapeutic Effects of (177)Lu-DOTA-M5A in Combination with Heat Shock Protein 90 Inhibitor Onalespib in Colorectal Cancer Xenografts

SIMPLE SUMMARY: Cancer treatment is hampered by the limitations of individual therapy modalities and the intricate nature of the disease. The administration of maximal monotherapy doses often leads to undesirable side effects and/or therapy resistance. As a result, there is a growing recognition of the importance of investigating combination therapy to effectively address these obstacles. In the present in vivo study, the therapeutic effects of combination therapy with the heat shock protein 90 inhibitor onalespib, a potential radiosensitizer, and (177)Lu-DOTA-M5A for colorectal cancer (CRC) treatment were explored for the first time. The results demonstrated that the combination treatment was so effective that retained or even superior therapeutic effects could be achieved with only half the dose of administered (177)Lu-DOTA-M5A, showing enhanced tumor growth suppression and increased apoptosis. Consequently, the combination therapy involving (177)Lu-DOTA-M5A and onalespib constitutes a promising approach for treating metastatic CRCs. By enhancing therapeutic effects, minimizing therapy resistance, and reducing side effects, this approach has the potential to expand the patient population that can benefit from targeted treatment. ABSTRACT: Carcinoembryonic antigen (CEA) has emerged as an attractive target for theranostic applications in colorectal cancers (CRCs). In the present study, the humanized anti-CEA antibody hT84.66-M5A (M5A) was labeled with (177)Lu for potential CRC therapy. Moreover, the novel combination of (177)Lu-DOTA-M5A with the heat shock protein 90 inhibitor onalespib, suggested to mediate radiosensitizing properties, was assessed in vivo for the first time. M5A antibody uptake and therapeutic effects, alone or in combination with onalespib, were assessed in human CRC xenografts and visualized using SPECT/CT imaging. Although both (177)Lu-DOTA-M5A and onalespib monotherapies effectively reduced tumor growth rates, the combination therapy demonstrated the most substantial impact, achieving a fourfold reduction in tumor growth compared to the control group. Median survival increased by 33% compared to (177)Lu-DOTA-M5A alone, and tripled compared to control and onalespib groups. Importantly, combination therapy yielded comparable or superior effects to the double dose of (177)Lu-DOTA-M5A monotherapy. (177)Lu-DOTA-M5A increased apoptotic cell levels, indicating its potential to induce tumor cell death. These findings show promise for (177)Lu-DOTA-M5A as a CRC therapeutic agent, and its combination with onalespib could significantly enhance treatment efficacy. Further in vivo studies are warranted to validate these findings fully and explore the treatment’s potential for clinical use.