Antagonizing CD105 enhances radiation sensitivity in prostate cancer

Abstract

Radiation therapy is the primary intervention for nearly half of the patients with localized advanced prostate cancer and standard of care for recurrent disease following surgery. The development of radiation resistant disease is an obstacle for nearly 30–50% of patients undergoing radiotherapy. A better understanding of mechanisms that lead to radiation resistance could aid in the development of sensitizing agents to improve outcome. Here, we identified a radiation-resistance pathway mediated by CD105, downstream of BMP and TGF-β signaling. Antagonizing CD105-dependent BMP signaling with a partially humanized monoclonal antibody, TRC105, resulted in a significant reduction in clonogenicity when combined with irradiation. In trying to better understand the mechanism for the radio-sensitization, we found that radiation-induced CD105/BMP signaling was sufficient and necessary for the upregulation of sirtuin1 (SIRT1) in contributing to p53 stabilization and PGC-1α activation. Combining TRC105 with irradiation delayed DNA damage repair compared to irradiation alone. However, in the absence of p53 function, combining TRC105 and radiation resulted in no reduction in clonogenicity compared to radiation alone, despite similar reduction of DNA damage repair observed in p53-intact cells. This suggested DNA damage repair was not the sole determinant of CD105 radio-resistance. As cancer cells undergo an energy deficit following irradiation, due to the demands of DNA and organelle repair, we examined SIRT1’s role on p53 and PGC-1α with respect to glycolysis and mitochondrial biogenesis, respectively. Consequently, blocking the CD105-SIRT1 axis was found to deplete the ATP stores of irradiated cells and cause G2 cell cycle arrest. Xenograft models supported these findings that combining TRC105 with irradiation significantly reduces tumor size over irradiation alone (p value = 10−9). We identified a novel synthetic lethality strategy of combining radiation and CD105 targeting to address the DNA repair and metabolic addiction induced by irradiation in p53-functional prostate cancers.

Endoglin Targeting: Lessons Learned and Questions That Remain

“…In the KEP1-11 breast cancer model, treatment with TRC105 reduced the presence of cancer-associated fibroblasts (CAFs) in primary tumors and reduced metastatic spread in an adjuvant setting [ 35 ]. In prostate cancer models, TRC105 treatment significantly potentiated the anti-tumor effects of radiation therapy, when compared to irradiation alone [ 48 ]. Additional research showed that the combination of androgen deprivation therapy (ADT) and TRC105 reduced castration-resistant prostate cancer progression through interruption of the communication between endoglin-expressing CAFs and prostate cancer cells [ 49 ].…”

HDAC2 Inhibitor Valproic Acid Increases Radiation Sensitivity of Drug-Resistant Melanoma Cells

“…Studies on cancers indicated that malfunctions of BMP signaling pathways were more or less responsible for alteration in therapeutic response and make cancer cell non responsive to inhibitor or radiation [15]. Some of the reports show that inhibition of BMP pathways sensitize cancer cells to radiation [16,17].…”

Soluble Endoglin (sCD105) as a Novel Biomarker for Detecting Aggressive Prostate Cancer

“…Endoglin may also represent a viable target to sensitize PC to various therapeutic modalities. Our group has previously demonstrated that radiation-resistance was mediated, in part, by CD105 downstream of the bone morphogenetic protein and transforming growth factor-β signaling whereas antagonizing CD105 with a new anti-angiogenic monoclonal antibody targeting CD105, TRC105, sensitized prostate tumors to the antitumor effects of radiation therapy in preclinical PC models in a p53-dependent manner (16). This study has several strengths and limitations.…”