Early Translational II
$1 663 549
Radiation therapy (RT) is an important curative treatment for several forms of cancers presenting in the head and neck sites. However, RT, even when delivered in a highly focused approach, can result in damage to the surrounding normal tissues, the most sensitive of which are the salivary glands. Over 70% of patients who receive RT for their head and neck cancer suffer from chronic dry mouth. Saliva is critical for many oral functions including chewing, eating, digesting food, swallowing and talking. Decreased saliva level therefore can result in severe dental decay, swallowing problem, speech difficulty and, in certain situations. chronic mouth pain and damage to the jaw bones. Currently, there is no effective medication to prevent or improve RT-related dry mouth. Even the most advanced and highly focused radiation techniques can only spare one but not all major salivary glands in the head and neck site. The glands that are important for saliva production at rest are the submandibular glands; however, they often cannot be spared from the radiation due to their location adjacent to tumor bearing lymph nodes. Therefore, there is a strong need to come up with a better treatment for RT-related dry mouth. Recently, stem cells have been identified to exist within the submandibular gland in mice. These cells, when put back into an irradiated submandibular gland, can form new gland tissues and produce saliva. We and others have found that such stem cells also exist in human submandibular gland. However, the number of these stem cells is quite low in adult glands, less than 0.3% in most cases. Therefore, we need to find a way to increase the number of stem cells isolated from the gland, store them, improve their survival when thawed and ensure that they develop into new gland tissues when injected into an irradiated glands. To address this, we plan to focus on the aldehyde dehydrogenase enzymes (ALDH), a family of proteins that are important for the survival and differentiation of normal tissue stem cells. We propose to identified a combination of ALDH activated drugs +/- fibroblast growth factor 10 (a growth factor involved in the development of salivary gland) in order to (1) increase the yield of these stem cells, (2) improve their survival in culture, specifically after multiple freeze/thaw cycles, and (3) enhance their ability to form actual salivary gland tissue and secrete saliva when placed back in irradiated mouse SMG and eventually human SMG. Our ultimate goal is to use these isolated huSMG SCs to restore saliva production in previously irradiated head and neck cancer patients.
Statement of Benefit to California:
Approximately 3500 Californians develop cancer that are located in the head and neck sites annually and most will required radiation treatment (RT) for their cancer. As a consequent, over 70% of these patients will develop dry mouth due to RT damage of their salivary glands. Chronic dry mouth then results in severe dental decay, swallowing difficulty, speech impairment and, in certain situation, chronic mouth pain and damage to the jaw bone. Currently, there is no effective drug for treatment of chronic dry mouth. Moreover, the monetary cost of temporary measures to improve saliva production and in managing the downstream health impact of chronic dry mouth such as dental repair and extractions, antibiotic use, surgical cost for jaw bone repair, hyperbaric oxygen treatments, acupuncture, etc, can be exorbitant and are often borne by patients, insurance and Californian taxpayers. This proposal, which focuses on improving the methods for isolating stem cells from adult submandibular glands and for placing them back into irradiated gland to restore function, will have a great impact on the management of post-radiation dry month. In theory, the stem cells from the same patients can be isolated, stored and placed back after the patients completes radiation therapy. Such an approach, if works, will provide a long-term cure for post-radiation dry mouth, improve quality of live in cancer survivors and minimizing the cost of managing dry mouth-related complication to the society.
This application describes a Development Candidate Feasibility (DCF) study, which explores the use of autologous submandibular gland stem cells (SMG SCs) to treat xerostomia resulting from radiotherapy. Xerostomia is defined as the lack of saliva or “dry mouth”. In Aim 1, the principal investigator (PI) proposes to identify the aldehyde dehydrogenase (ALDH) activator(s) with and without fibroblast growth factor 10 (FGF10) that i) can enrich for SMG SCs in vivo and ii) can enhance ex vivo expansion and promote differentiation in culture. In Aim 2 the PI proposes to investigate whether SMG SCs can restore function in an irradiated murine model, and to explore the effects of cryopreservation, timing of treatment, and co-treatment with factors identified in Aim 1. The reviewers agreed that the application’s objective is well defined, and if successful, could address an unmet medical need for patients following head and neck cancer treatment. While evidence presented to support the existence of SMG SCs was judged to be reasonable, reviewers felt that the rationale behind the use of ALDH activators and FGF10 is not strongly supported by the available data. Much of the plan was described as basic research in nature and that more fundamental biology needed to be worked out before proceeding with translational activities. Major concerns arose during the discussion of the application’s feasibility. The preliminary data support the existence of SMG SCs and the identification of novel activators of ALDH. However, several reviewers reiterated that the capacity for ALDH activators, as well as of FGF10, to induce SC enrichment, survival and engraftment has not been proven experimentally. All reviewers expressed concern that most of the screening studies proposed for factors important for SC enrichment, survival, and differentiation will be conducted using murine cells, which have inherent risk when translating to human cells. Furthermore, the PI has not shown that the in vivo model is well established with human cells. The potential pitfalls or alternative plans to address these issues are not properly discussed. Milestones were laid out for the murine work, but the jump to human cells and the groundwork for an IND are not laid out. These factors contributed to the reviewers’ perception that even as a DCF program (as submitted), the project would be unlikely to lead directly to translation. The reviewers stated that the research environment and institutional support are strong. Reviewers judged PI’s training and expertise in radiation biology to be excellent, but noted little experience with stem cell biology or regenerative medicine. Although the PI has committed 20% effort to the project, reviewers were concerned about the low percent effort commitment to the project from other senior team members, notably including the stem cell expert at only 1%. In summary, this application is for a DCF study that uses autologous SMG SCs to treat xerostomia resulting from radiotherapy. Although the proposal has a sound objective and potential impact, the reviewers had serious concerns regarding the rationale, feasibility, and the suitability of the PI to undertake this project. Thus, this application was not recommended for funding.
- Rainer Storb