Funding opportunities

Executive Summary The applicant proposes to bring together a multidisciplinary team dedicated to improving knowledge about the pathology and management of benign orofacial tumors. The applicant envisions a disease team that will address the problem of orofacial tumors in three components. A basic science component will investigate mechanisms by which stem cells contribute to tumor development. A second translational component will focus on the development of disease animal models to allow testing of novel stem cell based therapies while a third pre-clinical component will examine safety of the proposed stem cell therapy in preparation for phase I clinical studies. Reviewers noted that the program director has a strong track record in translating basic and preclinical observations into clinical studies through participation in several clinical studies and organization of several program projects. The proposed team has extensive preclinical experience using bone marrow derived mesenchymal stem cells for reconstruction of orofacial defects and interesting preliminary work on the tumor stem cells from ossifying fibroma. However, the concept proposed for a Disease Team is at an early exploratory stage of basic biological concepts and does not yet seem sufficiently mature to move to clinical trials within 5 years. Only minimal characterization of the proposed cells has been performed at this stage, which speaks to the lack of maturity of this project. A reviewer noted that the proposed experimental approaches are not adequately defined, and raised concern when considered along with lack of preliminary characterization of the non-malignant orofacial bone stem cells. The proposed planning process involves the establishment of research seminars, monthly conferences, an interactive website, and internal/external advisory committees. In addition, the applicant proposes to recruit an expert consultant in regulatory sciences, although this person is not named at this time. The distribution of skills amongst the proposed disease team appears to reflect an emphasis more on the basic research questions and less on the aim to investigate the efficacy and safety of stem cell based therapy on orofacial tumors. Reviewer Synopsis The PI, Dr Anh Le proposes to bring together a multidisciplinary team dedicated to improving knowledge about the pathology and management of benign orofacial tumors. Current standard of care typically involves radical surgical resection of the tumor which frequently results in facial disfigurement leading to psycho-social problems for the patient. The applicant envisions establishing a disease team that will address the problem of orofacial tumors in three components. A basic science component will investigate mechanisms by which stem cells contribute to tumor development. A second translational component will focus on the development of disease animal models to allow testing of novel stem cell based therapies while a third pre-clinical component will examine safety of the proposed stem cell therapy in preparation for phase I clinical studies. Reviewer One Comments Concept: The concept is “to investigate the functional role of tumor stem cells of benign tumors of orofacial bones, their local niche and interactions between cells and niche to elucidate the underlying mechanism of the benign but locally aggressive tumors with the ultimate goal of developing a less invasive novel stem cell based therapeutic approach for orofacial reconstruction”. Even though Dr. Le and the core disease team have extensive preclinical work using bone marrow derived mesenchymal stem cells for reconstruction of orofacial defects and interesting preliminary work on the tumor stem cells from ossifying fibroma, the science does not seem ripe for a push to clinical trials as yet. Principal Investigator: Dr. Le obtained her PhD in biology, DDS and certificate in Oral/Maxillofacial Surgery from UCLA. She is currently Associate Professor of Dentistry at USC. She has served as various elected positions, including President of the Oral and Maxillofacial Surgery Group of the International and American Associations of Dental Research. She has current NIH research funding, has conducted several NIH funded clinical studies and was PI on 2 Center Grants on Oral Health Disparities.. Planning Approach: The planning approach is described as a three pronged road map for the project leading to clinical trials. There does not seem to be a planning period in which to specify the gaps of knowledge but rather an exploratory period defining the cells. Reviewer Two Comments Concept: Current standard of care for the management of orofacial tumours is aggressive surgical resection that typically results in facial disfigurement and other debilitating sequelae. There is consequently a need to develop a cellular therapy to replace the tissue lost with this surgical intervention. However, a broader concept is being explored here one that encompasses studies of putative tumor stem cells, the development of disease animal models for testing of novel stem cell based therapies and preclinical studies to evaluate the efficacy of stem cell based therapies as a pre- requisite for phase I clinical studies. This concept, while laudable, seems overly broad when considered in the context of the expectation of clinical studies within 5 years. Principal Investigator: Dr. Le has a strong track record in translating basic and preclinical observations into clinical studies as evidenced by her participation in several clinical studies and her organisation of several programme projects. Dr. Le is very active in the oral and maxillofacial community and has previously served as President of the International American Association of Dental Research (IADR). In terms of her ability to assemble and lead a multi-disciplinary team, she has organized several program projects in past years, she is co-investigator on two center grants on oral health disparities and has submitted two clinical trials focusing on training residents on early detection and chemo-prevention and implementing tobacco cessation in minority smokers which has necessitated in her assembling a multi-disciplinary team of epidemiologists, pathologists and head/neck surgeons. Planning Approach: As noted above, the PI proposes a stem cell based treatment of orofacial tumors based on three projects. She has assembled a Disease Team comprising oral and maxillofacial, head and neck, plastic and craniofacial surgeons and stem cell and developmental biologists. One biomaterial engineer is included amongst the disease team. The distribution of skills amongst the disease team appears to reflect an emphasis more on project 1 and 2 than on project 3 which seeks to investigate the efficacy and safety of tem cell based therapy on orofacial tumors. This raises a concern as to the feasibility of stem cell based therapies being developed within a 5 year time frame. Reviewer Three Comments Concept: This grant concerns a novel approach designed to improve diagnosis and treatment of benign tumors of orofacial bones, which can be locally invasive and highly recurrent, in order to minimize unnecessary tissue removal and consequent disfigurement and associated problems. The significance of this problem is high, and the successful completion of the proposed studies would significantly improve our current knowledge of the behavior and characteristics of these stem cells. As stated by the PI, three major areas will be explored: 1) a solid basic science component focusing on the underlying mechanism of how stem cells contribute to benign orofacial tumors; 2) a translational component aimed at developing disease animal models for testing novel stem cell based–therapies; and 3) a pre-clinical component to test safety and efficacy of stem cell-based therapies in preparation for the early phase I treatment. The approach is designed to characterize stem cells resident in these benign orofacial bone tumors in order to better understand their properties, to develop tools with which to identify oral stem cells residing in non-malignant tumors, and to develop in vitro and in vivo models to study the behavior of these cells in tumor growth. The maturity of the proposed studies is modest, as evidenced by the fact that at this time, only minimal characterizations of these cells has been performed, apparently consisting of: identification of reduced runx2 expression in these cells; morphology identical to BMMSCs; and ability to form bone in an immunocompromised rat model. Demonstrated direct comparison of functional characterization of the presumed non-malignant orofacial bone tumor stem cells, and BMMSCs, would significantly strengthen this application. Principal Investigator: The PI, Dr. Anh Le, is a DDS and PhD, clinician-translational scientist trained in oral and maxillofacial surgery, with a solid background and extensive expertise in orofacial tumor biology and clinical research. Dr. Le has gathered an excellent Disease Team, consisting of clinicians, stem cell and developmental biology experts, oral pathologists, and biomaterial engineers, with extensive training and expertise in the proposed studies. Planning Approach: The proposed planning process will consist of establishing: 1) bimonthly research seminars and monthly conferences; 2) an interactive website; 3) establishment of Internal and External Advisory Committees; 4) and an expert consultant in Regulatory Sciences, although this person is not named at this time. It is proposed that the data generated in the proposed study will be used to support a pre-Investigational New Drug (IND) application for autologous somatic stem cell therapy, and also lead to a full IND application to the FDA for a clinical phase I trial in 4-5 years after the Planning Proposal award. The proposed experimental approaches are not well defined, which raises concern when considered along with lack of preliminary characterization of the non-malignant orofacial bone stem cells.