LOS ANGELES—For nearly half of the patients with localized advanced prostate cancer, radiation therapy is the primary intervention and standard of care for recurrent disease following surgery.
The problem is that nearly 30% to 50% of patients undergoing radiotherapy develop radiation-resistant disease, according to a study in the journal Oncogene.1
A research team from the Los Angeles VAMC and Cedars-Sinai Medical Center suggested that better understanding of mechanisms that lead to radiation resistance could aid in the development of sensitizing agents to improve outcome.
The researchers identified a radiation-resistance pathway mediated by CD105, downstream of BMP and TGF-β signaling. They found that 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 sirtuin 1 (SIRT1) in contributing to p53 stabilization and PGC-1α activation,” they wrote. “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.”
The authors said this finding “suggested DNA damage repair was not the sole determinant of CD105 radio-resistance.”
Cancer cells undergo an energy deficit following irradiation, due to the demands of DNA and organelle repair, and the study examined SIRT1’s role on p53 and PGC-1α in terms of glycolysis and mitochondrial biogenesis, respectively. Researchers determined that blocking the CD105-SIRT1 axis depleted the ATP stores of irradiated cells and caused 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), according to the authors, who concluded, “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.”
Madhav A, Andres A, Duong F, Mishra R, Haldar S, Liu Z, Angara B, Gottlieb R, Zumsteg ZS, Bhowmick NA. Antagonizing CD105 enhances radiation sensitivity in prostate cancer. Oncogene. 2018 Aug;37(32):4385-4397. doi: 10.1038/s41388-018-0278-0. Epub 2018 May 2. PubMed PMID: 29717261; PubMed Central PMCID: PMC6085281.