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Combination Therapy Improves Survival in Prostate Cancer Model

This section of prostate from a 13-week-old TRAMP mouse with a well-developed adenocarcinoma was stained with Twist, a transcription factor implicated in metastasis, and counter-stained with hematoxylin. Researchers have found that a vaccine against Twist, in combination with the androgen-receptor antagonist enzalutamide, more than doubled the survival rate of castration-resistant prostate cancer in mice.
This section of prostate from a 13-week-old TRAMP mouse with a well-developed adenocarcinoma was stained with Twist, a transcription factor implicated in metastasis, and counter-stained with hematoxylin. Researchers have found that a vaccine against Twist, in combination with the androgen-receptor antagonist enzalutamide, more than doubled the survival rate of castration-resistant prostate cancer in mice.

Surgery and radiotherapy are the recommended treatments for localized prostate cancer. Recurrent prostate cancer, however, is often treated with androgen-deprivation therapy. Most patients who undergo this type of therapy eventually develop castration-resistant prostate cancer (CRPC). Though initially androgen-related therapies for CRPC had been thought to be ineffective, further studies have demonstrated that the disease remains dependent on the signaling of androgens, such as testosterone, for its continued progression. This development suggests that alternative strategies for manipulating androgen signaling may prove useful for treating CRPC.

James Hodge, Ph.D., Head of the Recombinant Vaccine Group in CCR’s Laboratory of Tumor Immunology and Biology, and his colleagues have devised a therapy against CRPC that combines enzalutamide, an androgen-receptor antagonist, with a vaccine against Twist, a transcription factor implicated in cell mobility and metastasis. The researchers hypothesized that enzalutamide, which was previously shown effective in a preclinical prostate cancer trial and has been approved by the U.S. Food and Drug Administration for use in CRPC patients, may make prostate tumor cells more sensitive to attacks spearheaded by the immune system, such as an attack generated by vaccination to Twist. Furthermore, since interrupting androgen production activates thymus regeneration, the researchers thought enzalutamide could restore function to the thymus.

To test their hypothesis, the research team administered therapeutic oral doses of enzalutamide for two weeks to TRAMP (transgenic adenocarcinoma of the mouse prostate) mice, whose tumor progression closely resembles that of humans. The team observed that the treated mice had significant reductions in the weight of urinary and reproductive organs and significant increases in thymus weight compared to untreated animals. In addition, enzalutamide treatment significantly increased peripheral blood levels of T-cell receptor excision circles (TREC)—a marker of thymus function. Notably, enzalutamide spurred no proliferation in CD4+ T cells or CD8+ T cells, suggesting the drug does not activate the immune system.

The researchers found that Twist expression in the harvested prostates of TRAMP mice increased with disease progression. They also experimentally downregulated Twist with siRNA, causing a 45 percent reduction in Twist mRNA levels that corresponded to a 60 percent decrease in the migration of TRAMP-C2 cells. This result is consistent with previous reports implicating Twist in endothelial-to-mesenchymal transition, which results in increased cell motility coincident with metastasis.

Twist vaccination, administered to TRAMP mice by researchers once per week for 3 weeks, led to 8-fold and 2.5-fold increases relative to control of Twist-specific CD4+ T-cell proliferation—as measured in harvested spleen cells—in C57BL/6 and TRAMP mice, respectively. In additional experiments, Hodge’s team demonstrated that the combination of enzalutamide and Twist vaccine did not negatively affect the immunity generated by the Twist vaccine.

The researchers then tested the effectiveness of the combination of enzalutamide and Twist vaccine in four age groups of TRAMP mice, each representing more advanced stages of tumor progression: 11 weeks old; 17 weeks old; 25 weeks old; and 34 weeks old. These mice received treatment once a week for three months, every other week for three months, then monthly thereafter. Whereas enzalutamide given alone and Twist vaccination administered alone endowed no increase in survival rate, Hodge’s team found that relative to other treatments the enzalutamide-Twist vaccine combination therapy more than doubled the post-treatment survival rate—27.5 weeks vs. 10.3 weeks—in TRAMP mice. The researchers also observed enhanced treatment effectiveness in more progressive stages of the disease; mice with advanced-stage prostate tumors saw the greatest survival benefit.

Hodge and colleagues suggest that clinical trials employing enzalutamide may demonstrate additional effectiveness when combined with other immunotherapies such as the PROSTVAC-VF vaccine, which has shown effectiveness as a treatment of CRPC in phase 2 trials, reducing death rate by 44 percent and increasing survival by 8.5 months. An enzalutamide-PROSTVAC-VF combination therapy clinical trial for CRPC is currently underway at the NIH Clinical Center under the supervision of Ravi Madan, M.D., also in CCR’s Laboratory of Tumor Immunology and Biology.

Reviewed by Chris Palmer

Reference
Ardiani A, Farsaci B, Rogers CJ, Protter A, Guo Z, King TH, Apelian D, Hodge JW. Combination Therapy with a Second-Generation Androgen Receptor Antagonist and a Metastasis Vaccine Improves Survival in a Spontaneous Prostrate Cancer Model. Clinical Cancer Research, September 18, 2013. PubMed Link