New Drug Combination for Difficult-to-treat Double Negative Prostate Cancer

Physician consulting with a patients in hospital exam room.
Physician consulting with a patients in hospital exam room.

Researchers at The University of Texas MD Anderson Cancer Center have discovered how an aggressive form of prostate cancer called double-negative prostate cancer (DNPC) metastasizes by evading the immune system.

Based on a study funded by the National Institutes of Health (NIH), the Cancer Prevention and Research Institute of Texas and the MD Anderson Moon Shots Program®, the investigators reported on the pre-clinical development of a new therapy, which, when given in combination with existing immunotherapies, appears to stop and even reverse metastasis in mouse models.

The frequency of double-negative prostate cancer (DNPC) is increasing. The disease is difficult to treat and frequently arises in patients previously treated with therapies that inhibit androgen receptors (AR), known to spur prostate cancer cells growth.

Although androgen receptor signaling is a distinctive feature of prostate carcinoma and represents the major therapeutic target for treating metastatic prostate cancer, AR antagonism can contribute to the growth of  tumors that bypass a functional requirement for AR, often through neuroendocrine transdifferentiation.

Study findings were published in the July 18, 2019 online edition of Cancer Cell. [1]

Filippo G. Giancotti, M.D., Ph.D., is a physician-scientist with a deep interest in understanding the molecular changes that drive tumor progression and metastasis across cancer types and subtypes. His laboratory aims to elucidate the specific mechanisms that enable organ-specific colonization and identify biological mediators of these processes that can be targeted therapeutically.
Filippo G. Giancotti, M.D., Ph.D., is a physician-scientist with a deep interest in understanding the molecular changes that drive tumor progression and metastasis across cancer types and subtypes. His laboratory aims to elucidate the specific mechanisms that enable organ-specific colonization and identify biological mediators of these processes that can be targeted therapeutically.

In the published article, Filippo Giancotti, M.D., Ph.D., professor of Cancer Biology, reported that an epigenetic regulator known as the polycomb repressor complex 1 (PRC1) coordinates the initiation of metastasis by increasing the regenerative capacity of metastatic cells and by suppressing the immune system and spurring tumor blood vessel growth or angiogenesis.

New approaches
“The findings open up potential new approaches to treating DNPC, which has been recognized recently as a new subtype that emerges at least in part in response to treatment with next-generation AR inhibitors,” Giancotti noted.

“We showed that PRC1 plays a role with immunosuppression at metastatic sites in DNPC, and we developed a novel in-class inhibitor of PRC1. This inhibitor exhibited efficacy as a single treatment and cooperated with double checkpoint immunotherapy to completely suppress metastasis in pre-clinical DNPC models,” he added.

Through in vivo genetic screening, the team identified a cytokine called CCL2 as the major pro-metastatic gene induced by PRC1. CCL2 binds to a tumor cell receptor called CCR4 to boost regenerative capacity and to CCR2 in immune cells, creating an immunosuppressive microenvironment and boosting tumor blood vessel growth.

“CCL2 also attracts tumor-associated macrophages (TAMS) and regulatory T cells (Tregs), which suppresses the immune system and stimulates angiogenesis,” said Giancotti. “Our study showed that targeting PRC1 inhibits recruitment of TAMS and Tregs, suppressing tumor metastasis.”

Immunotherapy
Giancotti and his team combined PRC1 with two types of immunotherapy agents, which attracted important immune cells called CD4 and CD8 T cells, resulting in “maximal induction” of tumor cell death in mice.

“This indicates that the inhibiting TAMS and Tregs with PRC1 inhibitors enables double checkpoint therapy to not only recruit but also to activate T cells, thus causing metastasis regression,” said Giancotti.

Reference
[1] Su W, Han HH, Wang Y, Scher HI, Ouerfelli O, Giancotti FG. The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression. Cancer Cell, July 16, 2019. DOI:https://doi.org/10.1016/j.ccell.2019.06.009 [Article]