Funding opportunities

Development of Stem Cell-Based Therapies for Chemotherapy-induced Cognitive Impairments

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06382
Funds requested: 
$2 957 986
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Learning and memory defects (“chemo brain”) caused by drugs used for cancer treatment are rapidly emerging as a major clinical problem, with 1.5 million people being diagnosed with cancer every year in the U.S., of which more than 60% now survive for 20 years or more. There is no current treatment for these cognitive problems. Our research suggests that chemotherapy drugs affect the brain by reducing the number of synapses, which are the major means of communication among brain cells underlying learning and memory. Chemotherapy also damages and kills neural stem cells, the renewable resource that can generate new neurons to replace those damaged by chemotherapy. The long-term goal of our research is to develop a stem cell-based therapy that will replace the damaged synapses and repair the learning and memory deficits in our cancer patients. Our preliminary data in animal models of chemotherapy-induced impairment are very promising and suggest that this goal is possible. Research efforts will concentrate on defining the best strategy for treatment: using clinically compatible, transplantable neural stem cells generated from high-quality human pluripotent stem cell lines, or by means of a drug already in clinical use [Redacted], or a combination of these two approaches. The most active treatment found by our research will ultimately be chosen to test in patients diagnosed with chemotherapy-induced cognitive impairments.
Statement of Benefit to California: 
The California Department of Public Health states that over 1.2 million Californians who are alive today have a history of cancer. In 2012, about 150,000 Californians will be diagnosed with cancer. With the recent and significant progress made in cancer treatments, two out of three Californians who get cancer this year will be alive five years after diagnosis. Because the overwhelming majority of these patients are treated with chemotherapy, the potential risk of surviving the cancer but being disabled by learning and memory impairments is looming, both over our patients and their quality of life but also over our health care system. The majority of these patients will not be able to return to work, and will need expensive medical and social support. Consequently, the economic, social and medical costs associated with care for cancer survivors are significant. Estimates place the annual cost of cancer survivorship care in the United States in the billions of dollars. The development of a stem cell therapy for treatment of patients affected by severe chemotherapy-induced cognitive impairments will not only alleviate ongoing suffering, but also allow our patients (and their families) to return to work and contribute to California’s economy. Moreover, a stem cell-based therapy that will provide sustained recovery will reduce the ever-growing cost burden to the California cancer care system.
Review Summary: 
Executive Summary This application is focused on the development of human neural stem cell (hNSC) therapies for chemotherapy induced cognitive impairments, also known as chemo brain. Chemotherapy may cause learning and memory deficits by killing neural stem/progenitor cells or damaging specific components of neurons. The applicant hypothesizes that transplanted hNSCs could improve these cognitive deficits by cell replacement or growth factor secretion. There are four specific aims: 1) to develop and characterize an animal model of chemo brain; 2) to test hNSC transplant in this model; 3) to test a small molecule drug in the model; and 4) to test a combination therapy of hNSCs and the small molecule. Research Plan - There are insufficient preliminary data to justify the proposed studies, in particular the development of the animal model of chemo brain proposed in Aim 1. Behavioral data that show cognitive deficits persisting through the time points of proposed intervention are crucial to demonstrate feasibility of the project. - Reviewers described the overall approach as highly speculative, given the variety of damage that occurs following chemotherapy and the lack of supporting preliminary data. - The rationale for the proposed route of administration for hNSCs is not well justified. It is not clear how this route would enable cell integration in appropriate locations. In addition, potential adverse effects of transplanting cells by this route are not discussed. - Chemo brain is an important and growing unmet medical need without available treatment options. Principal Investigator (PI) - The PI is a well-trained neuro-oncologist with a strong clinical background and has been involved in multiple clinical trials as a PI and co-PI. - The PI has demonstrated success in terms of publications and funding but has a limited track record in translational research. - The PI does not have a proven track record as a stem cell biologist but has identified well-established mentors with appropriate stem cell expertise. Institutional Commitment - The environment at the applicant institution is excellent. - The institution has assured the PI of significant support and provided a modestly sized independent research space to support his/her research efforts. Responsiveness - The application is generally responsive to the RFA in its use of hNSCs and the translational focus of Aims 2-4. However, the small molecule focus of Aim 3 is not particularly responsive.
Conflicts: 

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