eNews August 17, 2016

Using Salmonella to target prostate tumors

Bacterial monotherapy as a cancer therapeutic

Finding therapies that destroy tumor cells while sparing normal ones remains the primary goal for many cancer researchers.  Many current clinical modalities are cytotoxic to normal cells, resulting in moderate to severe side effects in patients, including hair loss, sterility, and immunosuppression.  Research to develop therapies based on bacterial monotherapy, a treatment paradigm that originated more than a century ago, is making its resurgence.  In this strategy, patients are administered doses of attenuated or heat-inactivated bacteria which can grow and proliferate within tumor masses and lead to tumor-specific immune targeting.  Salmonella typhimurium is a bacterial strain that has been extensively researched for cancer-targeting applications.  Attenuated Salmonella strains can proliferate within host cells as well as infiltrate hypoxic tumor masses.  Further, various Salmonella strains are being developed that express advantageous alleles or even to deliver chemotherapeutic agents once they have colonized a tumor mass.  In a recent PLOSOne study, a research team from the University of Missouri led by Dr. Abraham Eisenstark employed a Salmonella strain that they developed, CRC2631, to target prostate tumors that arise in the TRAMP mouse model (C57BL/6-Tg(TRAMP)8247Ng/J, Stock #003135).  Weekly CRC2632 intraperitoneal injections into TRAMP transgenic males significantly reduced tumor size, but did not inhibit tumor progression.    This study opens the door for testing Salmonella-based monotherapies to treat cancer in humans. Further, combining such treatments with other therapies could improve outcomes for patients with certain cancer types.

CRC2631 reduces tumor burden in the TRAMP prostate tumor model

Hemizygous TRAMP males manifest progressive prostate tumors that begin as early prostatic intraepithelial neoplasia (PIN) and can progress to differentiated adenocarcinoma. Moreover, the tumors that originate in the prostate can metastasize to distant sites.  Adenocarcinomas are often detectable in TRAMP males by 24 weeks of age, and metastasis have been found as early as 30 weeks.  The CRC2631 Salmonella strain that Dr. Eisenstark’s lab used for their experiments is a variant of another Salmonella strain that had been shown previously to have antitumor activity. CRC2631 retains the tumor-killing activity of the parental strain in co-cultures with the human prostate cancer cell line, PC-3M, but is significantly less toxic to mice than the parental. 

In order to test the effects of CRC2631 on prostate tumor development, tumor burden, and animal survival, the Eisenstark team injected hemizygous TRAMP males with weekly intraperitoneal doses of CRC2631 (105-107 colony forming units (CFUs)),starting at 10 weeks of age.  After 13 weeks of treatment, surviving mice were sacrificed and examined for both prostatic and metastatic tumor burden.  Any tumors found were prepared for and histological analysis and severity grading. 

Overall, the mice tolerated the treatment well:  overall survival was similar for both vehicle-treated and CRC2631-treated groups over the study duration. Tumor volume in CRC2631-treated groups was reduced almost by 30% compared to vehicle-treated mice.  Across the dose range, however, no significant difference was observed: mice dosed with 105 or 107 CFUs showed the same reduction in tumor volume.  Moreover, the tumors that did form in mice across the different groups were of similar types, ranging from early PIN lesions to poorly differentiated neuroendocrine-type carcinoma. 

This study sets the groundwork for further pre-clinical testing with CRC2631 and other Salmonella substrains as tumor-targeting agents to treat prostate cancer.  Much work yet remains to better understand the mechanism of tumor-specific targeting by these bacteria and whether this kind of approach might be best suited to inclusion in combination therapies.   Any new tool in the arsenal to combat cancer, however, is always a step forward.

Reference

Kazmierczak RA et al. 2016. Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model. PLOSOne 11(8):e0160926. PMID: 27504973.