Prevention of Metastatic Breast Cancer with a TLR5 Agonist
Abstract
Cancer patients diagnosed with primary breast cancer often develop metastases, which is the result of the primary tumor spreading to other organs or tissues of the body. In the case of breast cancer, the liver is a major site for metastases and a major cause of fatality due to disruption of normal organ function and metabolism. Even if after surgical resection of primary breast tumor a patient is declared technically "disease free," there is still a significant risk of development of metastatic disease originating from disseminated tumor cells that can remain dormant for long periods of time and evade effective clearance by the immune system. Unfortunately, clinical responses of conventional treatments for these patients who have developed metastases have remained low due, in part, to significant drug-induced toxicities that severely limit use at levels below an optimal therapeutic dose-range. Therefore, the need for newer, more effective, and better tolerated therapeutic options for these patients has never been greater. "Immunotherapy" represents one such alternative approach, which is aimed at targeting the immune system towards recognition and eradication of tumor cells. The most powerful natural stimulators of immunity are the products of pathogenic microbes. In fact, our organism evolved to effectively recognize such products and to mobilize the immune system for efficient surveillance and eradication of parasites. Diverting the power of such an immune response towards cancer would greatly increase the chance for effective "cleaning" of our tissues from dormant tumor cells and thereby reducing the risk of development of breast tumor metastases. We found that bacterial protein flagellin, a well-known immunostimulator, is significantly less toxic but similarly or even more powerful than other innate immunity activators. The reason is that physiological response to flagellin is limited to a few organs capable of its recognition, the major of which is the liver and a site for breast cancer metastases. The uniqueness of flagellin led our team to find a drug mimicking its activity, and we developed Entolimod[TM], a modified flagellin derivative with significantly improved properties. Initially, Entolimod was under development as a radiation antidote to treat people following nuclear disasters. However, the powerful immunotherapeutic potential of Entolimod was later revealed: it was found capable of rescuing mice from liver metastases of breast, colon cancer, melanomas, and lymphomas. As our experiments showed, Entolimod acts by mobilizing cellular forces of innate immunity to the liver. High concentration of immune cells in the liver following Entolimod treatment enables recognition, eradication, and memorizing specific patterns of dormant tumor cells and micro-metastases by the immune system. Our objective is to convert these laboratory observations into effective methods of prevention and treatment of breast cancer metastasis. We propose a threefold (mechanistic, translational, and exploratory) approach to reach this goal. Our aims are: (1) to understand Entolimod s mechanism of action in order to fully reveal its therapeutic potential; (2) to develop assays for prediction and monitoring Entolimod s efficacy in humans by defining signs of human reaction to the drug, and (3) to explore whether Entolimod could be useful if applied in combination with anticancer vaccines. A success of this undertaking will allow us to address one of the Overarching Challenges: Eliminate the mortality associated with metastatic breast cancer. The data resulting from these studies will enable us to establish optimal strategy for clinical development of Entolimod towards Food and Drug Administration approval. Provided that the drug is currently in the end of the Phase I trial in cancer patients with advanced tumors, reaching approval stage can be projected to 2017-2019. Based on our current vision, we believe that, upon appro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510081
Entities
People
- Andrei Gudkov
Organizations
- United States Army