Login to Access Video or Poster Abstract: MP87-15
Sources of Funding: Supported by VA-Merit Award I01 BX 000766-01 (APK)

Introduction

Radiation therapy (RT) is a standard treatment for prostate cancer (PCA). Although dose escalation increases local control, further escalation hampers toxicity. Further improvement will be possible by addition of adjuvant therapies, which can synergize with radiation and thus improve efficacy.

Methods

Human prostate cancer cell lines were used to test the combination of radiation and (Nexrutine, Nx). Global transcriptome profiling was used to delineate the mechanism. Transgenic adenocarcinomas of mouse prostate (TRAMP) mice were treated with Nx or radiation alone, or combination of Nx plus radiation to assess Nx as a radiation adjuvant. Histopathology and immunohistochemistry of survival targets were used as primary and secondary outcomes respectively. Contingency table analysis with χ2 tests were used to characterize the differences in categorical factors between experimental groups. Means were compared and tested with independent t-test across experimental groups for continuous outcomes and repeated-measures. General linear modeling was used to examine treatment differences over time.

Results

We have identified ribosomal protein S6K (RPS6KB1) that is upregulated in prostate tumors and its expression is correlated with pathological stage. Knockdown of RPS6KB1 not only decreased colony forming ability of aggressive prostate cancer cells but also increased their sensitivity toward radiation-induced survival inhibition. Furthermore, we have identified a natural compound (Nexrutine, Nx) but not its biologically active components to inhibit the growth of prostate cancer cells in combination with radiation. Importantly, combination studies demonstrated strong synergistic interaction between Nx and radiation both in vitro in multiple prostate cancer cell lines and in vivo using TRAMP model. Mechanistic investigations including transcriptome analysis showed that RPS6KB1 as an important player in radio-resistance as well as in Nx-mediated radio-sensitization. Furthermore, Nx pretreatment prolongs G2/M checkpoint block following radiation by sustained activation of Wee1 kinase and phosphorylation of cdc2. Importantly cells pretreated with Nx showed increased staining for γ-H2AX relative to radiation alone suggesting that increased DNA damage. Remarkably all of these events lead to induction of apoptosis.

Conclusions

Taken together, this report provides scientific evidence in support of the use of Nx as an adjuvant in prostate cancer patients receiving radiotherapy and further emphasizes RPS6KB1 as a novel target for prostate cancer treatment. _x000D_

Funding

Supported by VA-Merit Award I01 BX 000766-01 (APK)