Funding opportunities

THERAPEUTIC OPPORTUNITIES TO TARGET TUMOR INITIATING CELLS IN SOLID TUMORS

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01477
Principle Investigator: 
Funds requested: 
$19 979 660
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Cancer is a major cause of human death worldwide. The vast majority of cancer patients suffer from solid tumors whose growth destroys vital organs. We propose to develop novel therapeutic drugs that target solid tumors affecting the brain, colon and ovaries. These cancers account for a significant proportion of currently intractable solid malignancies. Scientists have made great strides in understanding the molecular and cellular changes that cause cancer but the approval of new therapeutics that can specifically kill cancer cells has lagged behind. This disparity suggests that there must be critical bottlenecks impeding the process of turning a basic research discovery into a finished anti-cancer drug. Research over the past decade has given rise to the idea that one of these bottlenecks may be caused by the existence of cancer stem cells. According to the cancer stem cell hypothesis, there is a minor population of cancer stem cells that drives the growth of the entire tumor. However, cancer stem cells are very rare and hard to identify. Technical innovations have recently allowed the identification, isolation and growth of these cells in the laboratory, and it has become clear that they have properties that are distinct from both the bulk of tumor cells and the cancer cell lines usually used to test anticancer drug candidates. Furthermore, in the lab, cancer stem cells are resistant to the chemotherapy and radiation treatments used to kill most tumor cells. In a patient, cancer stem cells may not be killed by standard drugs and may eventually regrow the tumor, causing a cancer to relapse or spread. Thus, a drug that specifically targets cancer stem cells could dramatically improve the chances of treatment success. Our team is one of the few in the world that can identify cancer stem cells in brain, colon and ovarian tumors. Furthermore, we have developed assays that can accurately test the effectiveness of drug candidates in killing these cells. Our preliminary data suggest that our lead drug candidates can inhibit the growth of cancer stem cells in culture and block tumor initiation in animal models. Importantly, our drug candidates appear to work through mechanisms that are different from those employed by current chemotherapeutics, meaning that our drugs represent a fresh and potentially very effective approach to cancer treatment. Over the next several years, we propose to complete our development and preclinical studies of these drugs so that testing in cancer patients can begin.
Statement of Benefit to California: 
Our proposal may benefit the state of California in four important ways. First, solid tumors cause significant morbidity and mortality. We propose to develop 2-3 Investigational New Drugs (INDs) to treat colon, brain and ovarian tumors, which are often difficult to treat with conventional therapies and are associated with poor prognoses. Thus, the proposed INDs should lead to a decreased burden on the California health system. The second benefit arises from our novel approach to drug development, a route that other researchers may emulate. Most targeted cancer drugs fail in clinical trials, despite our growing knowledge of the molecular and cellular causes of cancer. These failures indicate that there are rate-limiting factors in the way basic research is currently translated to cancer drug discovery and development. One such factor may be related to a major new hypothesis in tumorigenesis, which states that a minor population of cancer initiating cells (CICs) drives bulk tumor growth. These CICs appear to survive existing therapies that kill most tumor cells, and so can go on to initiate relapses and metastases. A second rate-limiting factor may be the heterogeneity that exists both among and within different tumor types. Both of these “bottleneck” factors can be obviated by the molecular characterization and comparison of CICs and bulk tumor cells. Knowing the features that distinguish CICs from bulk tumor cells will facilitate a targeted drug development plan that optimizes chances for clinical success. We have devised such a strategy based on the integration of solutions to these limiting factors into a state-of-the-art drug discovery platform. This strategy may provide a foundation for the rapid extension of our approach to the treatment of other solid tumors. The third benefit is the linking of CIC identification to clinical outcome. The ability to isolate and propagate CICs from solid tumors is a recent innovation. We will perform a thorough genetic examination of the alterations in these cells that lead to oncogenesis. Because we intend to carry out this work in parallel with the characterization of tumor samples from patients with documented clinical outcomes, we will be able to correlate the nature of particular CICs with similarities/differences among human tumors in a way that identifies features statistically linked to poor outcomes. This information will allow the selection and validation of additional drugs so that a pipeline of ever more refined compounds is established even if initial attempts fail in the clinic. The fourth benefit falls directly in line with the focus of California’s robust biotechnology industry on drugs to address unmet medical needs. Our data and methods will be published and readily available, and so can be applied by existing and emerging biotech companies. Great advances in novel targeted therapeutics to treat solid tumors should be realized, expanding the drug development expertise of the state.
Review Summary: 
The goal of this proposal is to utilize a pipeline strategy to develop novel small molecule therapeutics targeting cancer-initiating cells (CICs) in solid tumor cancers. It is hypothesized that curative therapies for some solid tumor cancers have not been successful, in part, due to a population of stem cells in the bulk tumor, the CICs, that are resistant to current treatment regimens. The applicant suggests that the CICs are resistant due to physiological adaptations that have allowed them to survive in the tumor microenvironment. Based on this hypothesis, two drug targets have been selected for the development of small molecule therapeutics that would specifically target CICs, and the efficacy of these compounds will be evaluated in colon cancer, ovarian cancer, and glioblastoma. The applicant intends to unite a drug discovery program with cancer stem cell biologists and clinical research teams to develop and test the therapeutic candidates. Following the identification and optimization of a lead and a backup drug candidate for each drug target, the optimized compounds would be tested using both in vitro and in vivo platforms to assay the effect of the compounds on CICs and on tumor regression. The applicant proposes to define the patient population most likely to respond to each drug candidate by utilizing genomics to subcategorize the tumor subtypes in each of the three targeted solid tumor malignancies. The applicant also plans to evaluate each drug candidate in combination with the current standard-of-care treatments to demonstrate the distinct and/or synergistic mechanism of action of the proposed therapeutic compound. The applicant anticipates that Investigational New Drug (IND) applications for the two most promising candidates will be filed with the FDA by the end of the four-year program. The reviewers were enthusiastic about this proposal despite some concerns that the research plan was overly ambitious and that certain aspects of the proposal were not sufficiently mature scientifically. The reviewers determined that the proposed therapeutics, if successfully developed, would provide a significant clinical benefit to the patient population targeted in this proposal and recognized the unique capabilities of the assembled team to successfully identify and develop small molecule therapeutics. The reviewers agreed that the scientific rationale for drug target selection was reasonable. The targets are upregulated in certain tumors, their expression is associated with poor outcomes, and inhibitors of the drug targets have been shown to reduce proliferation of tumor cell lines. The reviewers noted the novel approach to drug development (targeting CIC in patients profiled by genomic analysis as potential responders) and that one of the drug targets appears to be uniquely targeted by this team. The reviewers expressed some concern with the rationale for the human stem cell component, commenting that there was little evidence provided that these drug targets regulate CICs in the bulk tumor. The reviewers also noted an inconsistency between the rationale and the preclinical plan; targets were selected based upon the hypothesis that the CICs have adapted to the tumor microenvironment and are, thereby, resistant to current treatment regimens; however, a plan to control the tumor microenvironment during testing of lead and backup compounds was not included. The preclinical research and development plan was well written and logical, and convincing preliminary data supported the drug development component. The reviewers remarked that the milestones for lead and back-up selection were appropriate and achievable. Reviewers had some concerns about the biological component of the preliminary results; although the applicants provide sufficient data demonstrating an association of the drug targets with solid tumors, the preliminary data supporting the role of these targets in the specific indications was limited, and the ovarian cancer indication was significantly underdeveloped. Furthermore, the efficacy data demonstrating the activity of the lead drug for the first target is only supported in colon cancer, and that data was not convincing as tumor regression was insufficiently monitored over time and following withdrawal of the drug. The reviewers considered the proposed project timelines to be ambitious. They were concerned that the difficulties in validating some of the proposed assays were not acknowledged in the timelines. Despite this concern, these assays were considered one of the strengths of the proposal, as was the applicant’s plan to test the proposed drug candidates in combination with current therapeutic regimens. Generally, reviewers praised the novel approach to drug development of targeting CICs and using genomics analysis of CIC lines and patient tumors to define a potentially responsive patient population. However, there was some concern that the extensive genomic studies were premature at this stage of research and might hinder the feasibility of filing an IND in the proposed timeline. The concerns regarding the timelines and feasibility of filing an IND were further complicated by the lack of a single therapeutic focus and the lack of scientific maturity in two of the three proposed indications. The reviewers agreed that it was likely the applicants could achieve an IND in the colon cancer indication and noted that the scope would be more manageable if the applicant focused only on this most scientifically mature indication. The large number of unknown factors, including the identity of the additional lead and back-up compounds and the identity of the patient population, were considered a barrier to a focus on optimization, validation and preclinical assessment of the current drug candidates. Reviewers further commented on the lack of details in the biological validation plans and the absence of a synopsis of preclinical studies and data analysis benchmarks. Some of the reviewers’ concerns regarding the feasibility of filing an IND in the proposed timeline were alleviated by the quality of the principal investigator (PI) and the impressive collaborative team. The PI, an established leader with an excellent track record in cancer research and drug development, is well suited to lead this team. The collaborative funding partner PI (Partner-PI) is a drug development expert with an equally impressive track record. The Co-PIs and senior investigators are highly experienced and qualified. The collaboration is reasonable and synergistic and brings together world leaders in cancer stem cells and medicinal chemistry to create a team with the appropriate translational experience, basic science expertise, and unique resources to carry out the proposed plan. The reviewers were also impressed with the evidence of collaboration and the excellent organizational structure of this team. The applicants developed an appropriate reporting structure and have good institutional support and resources. However, the leadership plan lacks a conflict resolution mechanism, and the applicant did not appoint an overall project manager. The reviewers noted that some of the budget requests were not appropriately justified. For example, it seems unlikely that all the personnel would be needed for all four years as lead and back-up candidates are optimized, assessed, and eliminated. Overall, reviewers considered this a well-written, high-impact proposal from an outstanding and collaborative team using innovative approaches to target common diseases with few therapeutic options. However, the reviewers’ enthusiasm was diminished somewhat by the a lack of scientific maturity and supportive preliminary data for some of the therapeutic indications, and the general consensus that the experimental plan was overly ambitious and would have been substantially improved by a singular focus on colon cancer. PROGRAMMATIC REVIEW A motion was made to move this application into Tier 1 - Recommended for Funding. Despite some reservations about the lack of focus and the overly ambitious research plan, the panel agreed that this application has the potential to significantly impact cancer treatment due to the unique nature of this collaboration and a platform that allows a distinctive approach to cancer research. The motion to move this application to Tier 1 carried.
Conflicts: 
  • Andrew Balber

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