Disease Team Planning
Treatment of benign, yet locally aggressive and highly recurrent tumors of the orofacial regions has been traditionally carried out, similar to other malignant diseases, with aggressive surgical removal resulting in major tissue loss, facial disfigurement, psychological and functionally debilitating sequelae. The overall goal of this proposal is to use new knowledge in stem cell biology to understand the behavior of these benign tumors and to develop new treatment approach using patient's own stem cells to restore defects in the orofacial regions. Our group has demonstrated promising evidences that certain benign tumors of the orofacial bones, possess stem cell properties and are capable of regenerating disease-like bone when transplanted into mice. To our knowledge, this is the first demonstration of the disease animal model generated by human tumor stem cells, which will allow clinical testing and further understanding of the cause of benign tumors of bones. We propose to investigate the functional role of tumor stem cells, their local environment, and their interactions to elucidate the underlying mechanism of benign/locally aggressive tumors of the orofacial bones, toward the development of a less invasive, novel stem cell-based therapeutic approach to allow a better tissue and functional preservation in the orofacial complex. The purpose of this planning grant is to bring together an outstanding, multidisciplinary Disease Team to develop a novel approach to treatment of benign orofacial tumors using the principles of stem cell biology associated with tumor pathology. The Disease Team will consist of experts in various clinical aspects of orofacial tumors, stem cell and developmental biologists, oral pathologists , and biomaterial engineers. Three major areas will be proposed: a solid basic science component focusing on the underlying mechanism of how stem cells contribute to benign orofacial tumors; a translational component aiming at development of disease animal models for testing novel stem cell based-therapies; and, a pre-clinical component to test safety and efficacy of stem cell-based therapies in preparation for the early clinical trial in the treatment of benign/locally invasive orofacial tumors.
Statement of Benefit to California:
There is a great clinical demand for developing more optimized approaches to repair facial defects caused by burns, trauma, genetic anomalies, and cancers. Benign tumors of the orofacial region are controversial in terms of treatment due to unknown pathology and unpredictable recurrence, and therefore, have been routinely managed aggressively with ablative surgical resection as malignant diseases, resulting in major tissue loss, facial disfigurement, psychological and functionally debilitating sequelae. The "safe margin" surgical approach reflects uncertainty and knowledge gap in tumor pathology and should be re-examined based on current knowledge of stem cell biology and organ development. A comprehensive understanding of the benign tumor disease will guide clinicians to refine current radical surgery towards a more tissue sparing/conserving approach, enable vital tissue preservation in the orofacial regions. More importantly, Californians who are head and neck tumor survivors, or suffer esthetic and functionally debilitating orofacial defects will benefit from the advances in stem cell biology and its clinical applications, specifically in the field of orofacial reconstruction. In this proposal, we will expand current knowledge of tumor stem cell biology to elucidate pathology of benign tumors and test the feasibility of utilizing autologous stem cells in the reconstruction of osseous and continuity defects of the orofacial complex. The refined stem cell-based approach in the treatment of benign/locally aggressive orofacial tumors will replace standard paradigm of treatment which involves multiple surgeries, lengthy operating time, cost, and morbidity to the patients. The success of this proposal will not only benefit the people of California, but will have high impact on the state economy by reducing the medical cost and overall financial burden on the State of California Health Insurance.
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.