Targeted Inhibitors of Tumorigenic and Immunosuppressive Signaling for Metastatic Prostate Cancer Therapy
Abstract
Immune cells have the power to detect and attack abnormal cancer cells, but they are often disabled by the tumor microenvironment and fail to attack. The STAT3 is an oncogenic protein commonly activated in the majority of human tumors, including prostate cancers. It contributes to cancer cell survival and plays a role of master regulator of immune suppression. STAT3 is an attractive but challenging target for pharmacological drugs. We previously showed that it is possible to use synthetic nucleic acids (oligonucleotides) to target STAT3 with high efficiency and precision. Small fragments of the DNA (CpG-molecules) can deliver STAT3-blocking oligonucleotides into specific target cells without need for any additional reagents and formulations. To generate CpG-STAT3 inhibitor that would be suitable for clinical application by routine intravenous injections, we generated two new strategies: (1) decoy molecule, which binds and inactivates STAT3 and (2) antisense oligonucleotide, which blocks production of STAT3. We confirmed that both types of CpG-STAT3 inhibitors can survive for several days in human serum and induce killing of metastatic prostate cancer cells. In addition, the same strategies can block STAT3 activity in the dysfunctional population of immune cells (myeloid-derived suppressor cells; MDSCs). The MDSCs block T cell activity and therefore are major hurdles in generating antitumor immune responses. Finally, we tested that CpG-STAT3 inhibitors injected intravenously reach target cells even in distant organs, such as bone marrow, which often harbor cancer metastases. Thus, we propose to develop a novel therapy to treat currently incurable metastatic prostate cancers. Our innovation lies in blocking STAT3 in cancer cells themselves and tumor-associated immune cells that feed tumors and shield them from immune responses. First, we plan to select the most stable CpG-STAT3 inhibitor design to enable intravenous injections of the drug to reach prostate tumor metastases and tumor-associated MDSCs. Our studies will determine the optimal regimen for treatments with CpG-STAT3 inhibitors to reach maximum direct killing of cancer cells while activating immune responses. Next, we will study effects of such oligonucleotides on prostate cancer cells, patients MDSCs, and finally in mice using both various prostate tumor models. These studies should provide us with information on CpG-STAT3 inhibitor effects, which will be later used to design the clinical CRPC immunotherapy. Prostate cancer remains the most common malignancy in men in the United States. Initial treatments of prostate cancers block hormone-mediated signals for tumor growth and metastasis; however, therapeutic effects are only temporary. The chemotherapy of metastatic prostate cancers is by no means curative while being highly toxic to normal tissues. The emerging cancer immunotherapies using antitumor vaccinations or antibodies to activate immune responses showed limited efficacy against CRPC. CpG-STAT3 inhibitors can overcome challenges in the immunotherapy of metastatic prostate cancers by weakening cancer cells and mounting highly specific immune attack. Such two-pronged attack on tumor and tumor-supporting immune cells should lead not only to tumor rejection but should also protect patient from cancer remission in the long term. The recent clinical genetic studies demonstrated that the lack of STAT3 protein is not deadly for humans, suggesting that drugs blocking STAT3 for short periods of time are not likely to generate severe toxic effects or autoimmune diseases. CpG and STAT3 inhibitors in the form of ASO and dODN molecules were well tolerated as single agents by patients. We expect that the successful completion of these studies, which align with the Fiscal Year 2015 Prostate Cancer Research Program Focus Area on Therapy and Mechanism of Resistance and Response, will generate novel, more effective, and safer therapeutics for CRPC pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610499
Entities
People
- Marcin Kortylewski
Organizations
- Beckman Research Institute of City of Hope
- United States Army