A important benefit of the tremendous progress in stem cell research has been the recognition that stem cell pathways are frequently re-activated in cancer cells conferring stem cell-like properties on a subset of tumor cells. This understanding is the basis for the emerging field of cancer stem cell (CSC) research.
The cancer stem cell paradigm is a new approach in cancer research that has profound implications for new anti-cancer drug development. It is now widely understood that tumors are comprised of different cell types. Experimental evidence has accumulated from many laboratories indicating that different tumor cells vary dramatically in their ability to grow a new tumor. The tumor cells capable of re-growing a new tumor are the CSCs, whereas the bulk of the tumor cells lack this capacity. This property of seeding new tumor growth is analogous to the growth of distant metastases that is a major cause of mortality in cancer patients. The highly tumorigenic cells CSCs share certain properties with normal stem cells, but have accumulated cancer causing mutations clearly making them abnormal. It is now widely appreciated that may current therapies fail to effectively target the CSC population, and thus the CSCs mediate recurrence of disease after treatment. New drugs that target CSCs to kill them or cause them to differentiate into less dangerous, non-tumorigenic cells have the potential to provide significant benefit to patients and to dramatically improve cancer treatment.
This project is focused on developing a new anti-cancer drug that has been shown to effectively block CSC self renewal in a variety of common types of cancer. New therapeutic agents that are effective in targeting cancer stem cells may reduce metastases and relapse after treatment thus providing a chance for improved long term survival of cancer patients. In the first phase of the project, we will complete the manufacturing of the drug for subsequent use in clinical trial and also execute safety studies that are necessary before initiating clinical trials. Next, we will test the safety of the drug in patients in Phase 1 clinical trials. Lastly, we will determine the efficacy in breast cancer patients in Phase 2 trials. This project will utilize innovative clinical trial designs to identify the patient populations most likely to benefit from treatment with this new treatment. We intend to focus our clinical testing on an important subset of women with breast cancer for whom effective therapies are currently lacking. Our project is a unique partnership of industry and academic researchers and clinicians dedicated to bringing new medicines to patients most in need of effective therapy.
This project will benefit the state of California and its citizens in several significant ways. The goal of the work funded by this grant is to develop a new cancer treatment. This agent attacks cancer stem cells - the most dangerous type of tumor cells because they have the unique ability to resist many current therapies and re-grow and metastasize to distant sites in the body. The funds from this study will be used to support innovative drug development and clinical testing in women with advanced breast cancer. Thus, this therapy will benefit cancer patients with a critical need for new treatment options. We have observed that agents that reduce cancer stem cells in tumors also inhibit the spread of metastatic disease. Patients with advanced cancers which have disseminated to distant organs typically require high cost hospital stays. Our new treatment is intended to ameliorate the incidence and relapse of metastatic cancer, thus reducing the requirement for hospitalization and associated specialized care for this class of advanced cancer patients.
In addition to the medical benefits of this project, funds from this grant will create and maintain high quality jobs in the state of California. California has been a recognized leader in biomedical research over the past several decades because of its excellent academic institutions and innovative companies attracting researchers from all over the country and the world. Many companies have made significant investments in establishing research facilities in California. Thus, biomedical research generates significant economic activity in the state. Continued leadership in the life sciences field relies on being at the forefront of cutting edge fields that are focal points of research interest and investment. Novel anti-cancer therapeutics, in general, and cancer stem cell-based therapeutic approaches, in particular, are excellent examples of important and innovative directions in drug development. CIRM will provide an important source of funding to support cancer stem cell therapeutics which hold the promise of becoming breakthrough medications in cancer treatment.
The goal of this research is to develop and clinically evaluate a new treatment for breast cancer patients by targeting the cancer stem cells (CSCs) that are reputed to cause recurrence of their disease. The therapeutic candidate is a monoclonal antibody (mAb) targeting a signaling pathway involved in CSC self-renewal, thereby inhibiting a key signaling pathway that is frequently dysregulated in multiple cancer types. Early project activities will focus on completing preclinical development and filing an Investigational New Drug (IND) application with the Food and Drug Administration (FDA). Subsequent objectives are to evaluate safety in Phase I clinical trials and to complete the enrollment phase of a Phase II study for determining efficacy in breast cancer patients.
Significance and Impact
- This therapy specifically aims at cancer stem cells that cause tumor recurrence following conventional care. If effective, this approach could potentially be used against other types of cancers in which CSCs are implicated.
- The proposed therapeutic addresses a clear unmet need, as the proposed breast cancer patient population has one of the worst prognosises and a very limited set of options for effective treatment.
- The clinical competitiveness of the proposed therapeutic is excellent. Other agents targeting this signaling pathway have shown dose limiting gastrointestinal toxicity, likely due to general effects on other protein family members. By enabling more specific targeting, the proposed approach may improve the therapeutic index significantly.
Project Rationale and Feasibility
- This application describes a mature development candidate that is poised to move into IND-enabling studies. The clinical program is ambitious but achievable, and the Gantt chart and timelines are detailed and appropriate.
- The proposed studies are rigorous and well designed to directly test the hypothesis put forth by the applicant.
- The applicant has provided robust and compelling preclinical data to demonstrate activity of the proposed mAb against CSCs. However, tumor recurrence was decreased but not eliminated, and therefore the extent to which clinical benefit would be observed was not clear to all reviewers.
- Preliminary data on the activity of the proposed therapeutic against colon cancer and other cell types is interesting and adds weight to the underlying rationale. Reviewer confidence would have been bolstered, however, by inclusion of data demonstrating anti-CSC activity specifically in breast cancer.
- It was noted that the distribution of expression of the antibody target protein in various cancers (breast, colon, lung etc.) and normal tissues had not been discussed and that the in-vitro efficacy of the mAb on the viability of the CD44+, CD24 low stem cells would have been valuable for demonstrating its specificity.
-Data on the stability of the aqueous dosage form was not described; reviewers recommended that this information be obtained prior to IND filing.
Principal Investigator (PI) and Planning Leader
- The PI has substantial leadership experience and has worked successfully in drug development for almost two decades.
- The PI has an excellent background in developing CSC targeting mAbs and several have entered clinical testing.
- As no Planning Leader has been specified, it is presumed that the PI will serve in that capacity. He/she has excellent and appropriate qualifications to do so.