New theranostic shows promise for treating triple-negative breast cancer

Specifically, Li radiolabeled diZD, a vascular endothelial growth factor receptor (VEGFR) targeting agent with ¹⁷⁷Lu for an angiogenesis-based TRT and 64Cu for positron emission tomography (PET) imaging in a preclinical TNBC murine model. Cell binding assays confirmed specificity and equivalent binding affinities of both ¹⁷⁷Lu-DOTA-diZD and similarly constructed ⁶⁴Cu-DOTA-diZD to cellular VEGFR2. Moreover, the binding of either of these was significantly enhanced relative to the parental drug compound ZD6474. This ⁶⁴Cu/¹⁷⁷Lu-DOTA-diZD theranostic pair demonstrated a notable antitumor efficacy, enhanced local tumor control, and greater survival rates in 4T1 tumor mouse models. PET imaging revealed a surging diZD accumulation in the tumor of mice from 6 hours to 24 hours post-injection peaking at 48 hours. Further, diagnostic imaging of the ⁶⁴Cu-DOTA-diZD revealed marked uptake in lung metastatic lesions as well as the lungs themselves suggesting a potential for both primary and metastatic tumor TRT using ¹⁷⁷Lu-DOTA-diZD. The volume of the tumors in 4T1 mice treated with ¹⁷⁷Lu-DOTA-diZD were significantly reduced and survived significantly longer before reaching the study endpoint without systemic toxicity, relative to controls. Antibody-based TRT for TNBC includes the immune checkpoint inhibitor against the programmed death receptor 1 (PD1). PD1 is expressed on the surface of tumor cells and is centrally involved in the tumor-induced suppression of the immune system. To contrast the potency of the ⁶⁴Cu/¹⁷⁷Lu-DOTA-diZD TRT treatment with the anti-PD1 antibody immunotherapy, Li performed several comparative studies. First, expression of the proliferation biomarker Ki67 was markedly diminished in tumor tissues of 4T1 mice treated with ¹⁷⁷Lu-DOTA-diZD, although it was present in the same treated with anti-PD1 immunotherapy. Second, CD4+ and CD8+ cell populations doubled post treatment with ¹⁷⁷Lu-DOTA-diZD TRT whereas only a slim increase in these cell populations was observed post-treatment with anti-PD1 immunotherapy. This indicated that the anti-PD1 antibodies elicited a poor response in the 4T1 tumor-bearing mice. These results also shed light on a possible mechanism of action of the ¹⁷⁷Lu-DOTA-diZD molecule – tumor microenvironment modulation and triggering of the adaptive immune response. It is unclear if TRT and anti-PD1 immunotherapy can complement each other in terms of producing better treatment outcomes. It is speculated that radiation therapy inflects the tumor microenvironment and triggers the adaptive immune response, leading to infiltration of active immune cells and hence a better response to immunotherapy. However, studies of combinatorial therapies reveal disparate results. Studies on an immunoresponsive colon cancer model suggested improved survival and long-term tumor control with concurrent TRT/anti-PD1 immunotherapy as compared with sequential therapy. Further investigation on the potentials of TRT/anti-PD1 combinatorial immunotherapy with an emphasis on the optimization of the sequence or timing of administration is imperative.

Yuqian Huang, Zhen Yang, Feng Li, Hong Zhao, Chun Li, Nam Yu, Dale J Hamilton, Zheng Li. ⁶⁴ Cu/ ¹⁷⁷ Lu-DOTA-diZD, a Small-Molecule-Based Theranostic Pair for Triple-Negative Breast Cancer. J Med Chem. 2021 Mar 11;64(5):2705-2713. doi: 10.1021/acs.jmedchem.0c01957. This work was supported by the Houston Methodist Research Institute (HMRI) and foundation. The authors thank the preclinical imaging core facility of HMRI. This research was funded in part through DoD BCRP Breakthrough Award (BC141561P1) (Z.L.) and Finger Distinguished Endowed Chair (D.H.).