Funding opportunities

Stem Cell-Mediated Oncocidal Therapy of Primary & Metastatic Brain Tumors

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00696
Principle Investigator: 
Funds requested: 
$55 000
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Brain tumors (BTs) are incurable, whether they start in the brain or spread there from other sites (e.g., lung, colon, breast, skin). Indeed, the latter situation is even more common & often more frustrating – although we’ve made inroads in treating such non-neural cancers, once brain metastases are discovered, hope is largely abandoned. Current therapies are limited by their inability to reach widely disseminated tumor cells that become insinuated within normal brain structures. Despite advances in surgical, radiation, pharmacologic, & gene therapies, survival with a BT remains dismal. Interestingly, the property that might circumvent this major obstacle to therapy – i.e., delivery of therapeutic molecules to the cells that need to be eliminated -- matches one of the better accepted attributes of the neural stem cell (NSC) – an attraction (over even great distances) for sites of pathology in the adult brain, including primary & metastatic cancer. If armed with a proper tumor-killing gene, the NSCs (whether administered into the brain or into the bloodstream), when drawn to these cancers, will dramatically reduce the tumor burden, including even single invading tumor cells, in a manner heretofore unachieved. The NSCs perform this action without themselves becoming tumorigenic or augmenting the pre-existing tumor. This phenomenon was 1st revealed by researchers on this proposed team. (In fact, the concepts have been extended to many other kinds of diseases.) In this proposal, a number of authentic mouse models of primary & metastatic BTs (including breast cancer) will be used (for this particular condition, we will not need a large animal model prior to clinical trials). Human NSCs (hNSCs) will be derived from 5 distinct sources, all have been proffered as being therapeutic but have never been compared head-to-head. Similarly a variety of potential hNSC-mediated therapeutic mechanisms will be compared. We anticipate a clinical trial of 1 or more of these cellular vehicles armed with the most effective gene for patients with intracranial BTs within ~3 yrs. Members of this proposed team have experience in bringing cancer therapies to clinical trial, hold the IP surrounding the use of stem cells against cancer, have begun negotiations with regulatory agencies, & have enlisted a GMP facility. Because immunocompatibility of the hNSCs with the recipient is not a concern in BT therapy, a limited number of hNSC lines need be developed for all prospective patients. Furthermore, BT treatment does not require long-term NSC survival or connectivity; can be piggy-backed onto present therapeutic regimes; is amenable to real-time imaging. Therefore, taken together, BTs may be the low hanging fruit of stem cell therapies. These concepts may ultimately be applicable to many kinds of cancers throughout the body using a range of different kinds of stem cells.
Statement of Benefit to California: 
Brain tumors (BTs) are incurable, whether they start in the brain or spread there from other sites (e.g., lung, colon, breast, skin). Indeed, the latter situation is even more common & often more frustrating – although we’ve made inroads in treating such non-neural cancers, once brain metastases are discovered, hope is largely abandoned. The emotional & financial burden on California citizenry (the patients, their families, & the health care system) is immense. Despite advances in surgical, radiation, pharmacologic, & gene therapies, survival remains dismal. Current therapies are limited by their inability to reach widely disseminated tumor cells that become insinuated within normal brain structures. Interestingly, the property that might circumvent this obstacle to cure – i.e., delivery of therapeutic molecules to the cells that need to be eliminated -- matches one of the better accepted attributes of the neural stem cell (NSC) – an attraction (over even great distances) for sites of pathology. If armed with a proper tumor-killing gene, the NSCs (whether administered into the brain or into the bloodstream), when drawn to these cancers, will dramatically reduce the tumor burden, including even single invading tumor cells, in a manner heretofore unachieved. It has been suggested that BTs re-engage certain developmental programs operative in normal stem cells, hence making the latter well-poised to “hunt down” the latter because they might be responding to similar cues. (This “pathotropic” property of stem cells, first unveiled by members of this proposed team as been extended to many other kinds of diseases.) The concepts proposed in this application are eminently responsive to the RFA’s goals in that they are mature & exploit known stem cell properties to address a therapeutic gap for a devastating disease unmet by extant approaches. BTs may be the low hanging fruit of stem cell therapies. The chances of a success – hence bringing credit to California’s wisdom in passing Prop. 71 – are high (in part because the bar for success is so tragically low). We anticipate a clinical trial of a stem-cell based therapy for patients with intracranial BTs within ~3 yrs. Furthermore, this approach may ultimately be applicable to many types of cancers throughout the body using a range of different kinds of stem cells, a speculation already being validated by investigators & companies worldwide. If true, California may emerge as even a more prominent “Mecca” for cutting-edge cancer therapies. Furthermore, investigators on this proposed team have begun to understand some of the cues mediating the homing of NSCs to cancer. Although our initial clinical trial will focus on delivering genes already known to be effectively tumoricidal, new insights into the mechanisms underlying homing & metastasis may help identify novel therapeutic targets. Such insights could give rise to new intellectual property, in which California would be a stakeholder.
Review Summary: 
Executive Summary This applicant proposes to organize a team of researchers in the area of primary and metastatic brain tumors, to develop therapies for glioma and non-neural neoplasms that metastasize to the brain. The applicants propose to test the interaction between a wide variety of neural cells and tumor cells including cells of both central nervous system (CNS) and non-neural origin. In particular, the applicants propose to determine the extent to which these different transplanted cells can migrate into regions of tumor and then deliver a cytotoxic agent to destroy tumor cells. Tumors affecting the CNS are incurable, and current therapies are limited by their inability to reach tumor cells disseminated throughout normal brain structures. The application of stem cells (SCs) to brain tumor therapy is undoubtedly of great medical significance and could advance SC therapies, and reviewers commented on the potential to treat tumor cells that have migrated away from tumor masses and infiltrated the surrounding brain. The use of SCs to track brain tumor cells has significant support from the series of publications from the investigators included in this group. Similarly, the use of SCs to induce cytotoxic effects is supported by publications from this group. While there remain a few unresolved issues that could affect the stated timetable for initiation of the first clinical trial, many of these issues can be addressed and would not preclude a clinical trial based on these studies within 5 years. Many aspects of the proposal are well developed and mature, and the likelihood of a clinical trial arising from this work is enhanced by the multiple steps the group has already taken to address the necessary regulatory elements. Among the greatest strengths of this proposal is the leadership of the PI and the superb research team. The PI is a world-renowned leader in neuro-oncology. S/he has a very long track record in fundamental studies of CNS oncogenesis, has published nearly 300 scientific papers, and is a member of the National Academy of Sciences. The PI has assembled a highly impressive group of clinicians and scientists with broad expertise in CNS oncology, SC biology, cancer SCs, oncolytic chemotherapeutic agents, neurosurgery, imaging, clinical trial design, and good manufacturing protocol (GMP) regulation. The planning approach builds on the substantial published studies of the group. The group clearly has all the expertise required to advance the plan as stated, and has a very high likelihood of being in a position to apply for a Disease Team Research Award. The plan is very mature with regard to the objectives of preclinical studies, how the lab-based work will be delegated, and how the group will work together to develop a clinical trial. The applicant proposes to organize a multi-investigator meeting to co-ordinate the process. S/he has listed a large number of skills that would contribute to such a meeting, and for each of these s/he has (as above mentioned) listed various experts in the fields who would be included in this team approach. Importantly s/he has also identified an advisory board that would oversee the project, including again those experienced in surgery, animal models, gene therapies, and cancer SCs. The plan could be strengthened by a more complete discussion of glioma biology and by efforts to broaden the potential target profile to include pathways identified as important to gliomagenesis. Alternatively, if these targets are not to be utilized, the applicant should include a discussion of why they are not appropriate and why the chosen targets have a greater likelihood of success. In addition, a more detailed discussion of which glioma models (specific cell lines or primary isolates) are to be utilized and why would provide additional support to the proposal, as it strengthens the relatedness of these studies to human disease. Ultimately, this may be a very difficult target in terms of both identifying the cells, assuming they themselves don’t become tumorigenic (which was not addressed in the proposal), and determining how they will be used in the various ways outlined for clinical use. Nevertheless, the planning meetings proposed are critical for starting through these issues. The investigator has outlined a project plan, a meeting plan, and a group of investigators, has developed a rough timetable for meetings, and will very likely be able to lead this team and bring any appropriate findings to a clinical trial. For these reasons, and because of the high medical significance of the proposed research, the review panel was supportive of the application being funded. Reviewer One Comments Concept: The use of stem cells to track brain tumor cells has significant support in the series of publications from the investigators included in this group. Similarly, the use of stem cells to induce cytotoxic effects has support in publications from this group. While these aspects of the proposal are well developed and mature, there remain a few unresolved issues that could affect the stated timetable for initiation of the first clinical trial (3 years). These issues can be addressed and would not preclude a clinical trial based on these studies within 5 years. The likelihood of a clinical trial arising from this work is enhanced by the multiple steps the group has already taken to address the necessary regulatory elements. The application of stem cells to brain tumor therapy is undoubtedly a critical medical problem that can advance stem cell therapies. Specific concerns with the experimental plan are as follows: • While stem cells as a delivery system for tumoricidal therapy is well supported, the therapeutic target is less mature. The molecular basis for high-grade glioma formation and growth is a relatively well-developed field that has very recently been further advanced by The Cancer genome Atlas. The role of EGF receptor and PTEN as well as mutations in the Rb and p53 pathways is well described. The value of stem cell-based therapy may lie in the ability to treat tumor cells that have migrated away from tumor masses and infiltrated the surrounding brain. These cells possess these genetic alterations. This project would be strengthened by efforts to broaden the potential target profile to include pathways identified as important to gliomagenesis. • The investigators state that it will be possible to “piggyback” stem cell therapies with more standard approaches to malignant glioma treatment. They also state the migration of stem cells is directed, at least in part, by inflammatory mediators. Virtually all patients with high-grade glioma receive radiation therapy. Radiation therapy induces an inflammatory response that will render large areas of the brain “pathological”. There are no data described in this proposal regarding what effect this might have on the homing of stem cells, or how this might impact on the timing of stem cell therapy. This issue may need to be resolved prior to clinical trial. • The authors state in the abstract and in the proposal that “because immunocompatibility of the human neural stem cells (hNSCs) with the recipient is not a concern” but then in Table 2 state “immune rejection of NSCs would probably enhance their tumor-killing ability”. If an immune response is stimulated in the brain there would be a risk for collateral damage to the brain as occurs in infection and auto-immune disease. This may need to be better defined prior to clinical trial. • The authors will use an activated Ras model and a xenograft model of high-grade glioma in these studies. It is not clear what cells will be used for xenografts. Will there be several different cell lines? Will there be primary xenografts? Will these include cells derived from both primary and secondary glioblastoma (GBM)? When NSCs are implanted into the brains of activated Ras mice, how will the tracking of stem cells to infiltrating tumor cells be accomplished, as the Ras-induced tumor cells will not express green fluorescent protein (GFP)? Principal Investigator: Among the greatest strengths of this proposal is the leadership of the PI and superb research team. Dr Cavenee is a world-renowned leader in neuro-oncology who undoubtedly will be able to lead this team and bring any appropriate findings to clinical trial. Planning Approach: The planning approach builds on the substantial published studies of the group. The group clearly has all the expertise to advance the plan as stated and has a very high likelihood of being in a position to successfully apply for a Disease Team Research Award. The plan is very mature with regard to the objectives of preclinical studies, how the lab-based work will be delegated and how the group will work together to develop a clinical trial. As stated above, the plan could be strengthened by a more complete discussion of glioma biology and the potential to target the known biological basis of glioma. Alternatively, if these targets are not to be utilized, a discussion of why they are not appropriate, and why the chosen targets have a greater likelihood of success. In addition, a more detailed discussion of which glioma models (specific cell lines or primary isolates) are to be utilized and why, would provide additional support to the proposal as it strengthen the relatedness of these studies to human disease. Reviewer Two Comments Concept: This proposal will focus on treatment approaches towards gliomas. Both gliomas and non-neural neoplasms that metastasize to the CNS are untreatable and uniformly fatal. Current therapies have major limitations in spite of recent advances in surgical radiation and pharmacologic approaches. In recent years it’s been clear that stem cells particularly neuron stem cells have the ability to “home” towards primary metastatic brain tumors following intracranial, intravascular administration at least in animal models. Neural stem cells (NCs) have been engineered to deliver a range of various oncolytic genes that can effectively and safely reduce tumor burden. In fact, transgenic mice that spontaneously develop brain tumors as well as immunoincompetent mice with neoplastic xenografts have served as preclinical models for invasive gliomas. The team is planning to derive human neural stem cells (hNSCs) from 5 distant sources including human embryonic stem cells (hESCs), fetal CNS tissue, adult CNS tissue, adult bone marrow and amniotic cells. Although, they all have been proposed to be potentially therapeutic they never been compared on a head-to-head basis. Currently tools can be employed such as studying in real time by MRI or bioluminescence the tracking of tumors of human stem cells. This group plans then to investigate these approaches towards the use of stem cells against brain cancers with a team experienced in clinical trials of brain cancer therapies as well as those holding appropriate intellectual property on the use of stem cells. Principal Investigator: fine Planning Approach: Overall it may be timely to begin to integrate the various approaches to neuronal stem cells and brain tumors as therapeutic tools. Whether or not these cells will act as homing cells for identification of tumors as well as delivery of therapeutic agents remains unknown and a number of investigators are proposed to gather for periodic meetings to investigate such an approach. There’s no question that there are major hurdles to the realization of this approach for particular brain tumor therapy, however the only way to realistically approach this is to begin to plan a multi investigator meeting. To that end the PI has listed a large number of investigators who can participate is such a meeting including, identifying the various skills or resources that are critical such as CNS oncology, stem cell biology, cancer stem cells, metastatic chemistry, micro RNAi, brain metastatic models, neurosurgical approaches, GMP approaches, imaging approaches and for each of these he has listed various experts in the fields who would be included in this team approach. Importantly he has also identified an advisory board that would oversee externally this approach including again those experienced in surgery, animal models, gene therapies, and cancer stem cells. Although, ultimately this may be a very difficult target in terms of both identifying the cells assuming they themselves don’t become tumorigenic and how they would be used in various ways outlined for clinic use. It’s far simpler when a much more focused approach is planned over multiple years while in this proposal many, many different approaches are being envisioned which could ultimately hinder a focused approach. Never the less these planning meetings are critical for starting through these issues. Overall the investigator has identified both a plan, a meeting plan, a group of investigators as well as relative crudely outlined time table for meetings. Reviewer Three Comments Concept: Brain cancer of both CNS and metastatic origin remains a large unmet clinical need. A number of studies have shown that, following transplantation of tumor cells into rodent brain, the tumor cells activate either endogenous NSCs or transplanted NSCs and induce the selective migration of both populations into regions of tumor. In this proposal, the applicants intend to compare the tropism of CNS or metastatic tumor cells on several different human neural stem cell populations including those derived from adult human and fetal brain, human ES cells, adult human bone marrow, and stem cells derived from amniotic fluid. Once the optimal neural stem cell population has been obtained and its migratory capacity has been identified, these cells will be genetically engineered to deliver cytotoxic agents to tumor cells and the ability of these cells to deliver these agents to tumor cells will be assessed. Following this, the applicants propose to develop an IND to generate a clinical protocol for using human neural stem cells prepared under GMP as a therapy for human brain cancer. Principal Investigator: The principal investigator is an internationally recognized expert in brain cell biology. He has a very long track record in fundamental studies of CNS oncogenesis. He has published nearly 300 scientific papers and is a member of the National Academy of Science. He has assembled a highly impressive grouping of clinicians and scientists with broad expertise in CNS oncology, stem cell biology, cancer stem cells, oncolytic chemotherapeutic agents, neurosurgery, imaging, clinical trial design, and GMP regulation. Planning Approach: The translational approach outlined in this proposal is very straightforward and builds nicely upon already extensive work of the P.I and members of the research team, There is a broad breadth of complementary skills that suggest that this could be a very highly successful strategy for treating brain tumors.
Conflicts: 

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