Early Translational II
High rates of mortality convert malignant glioma into the third leading cause of cancer-related death among men 15-54 years of age and the fourth leading cause of death for women 15-34 years of age. Among children less than 15 years of age, the impact of central nervous system cancer is even more pronounced. Primary brain tumors are actually the most common solid tumor of childhood and the second leading cause of cancer death after leukemia. The toxicity of current treatments causes serious life-long effects in the very few patients who survive. However, glioma is not presently a primary research focus for pharmaceutical companies. Recent research has found that gliomas are driven by a small group of cells inside the tumor that behave like stem cells. These cells have some of the same marker molecules on their surface as do normal nervous system stem cells. These “cancer stem cells” divide to produce most of the cells in a brain tumor, and they also divide to make more cancer stem cells. What makes these glioma cancer stem cells dangerous is that they invade normal brain tissue adjacent to the tumor and they are very resistant to standard chemotherapy and radiation therapy used to treat the brain cancer. So even though therapy might kill many of the cells in the brain tumor, the glioma cancer stem cells survive, continuing to divide and invade normal brain tissue. Therefore, a potentially very effective strategy may be to disrupt or destroy the glioma cancer stem cells. There are molecules of central importance in nervous system stem cell biology. These molecules participate in the elaboration of tissue in the developing nervous system. They are found in very high levels in glioma cancer stem cells. We know that if we use genetic ways of blocking these molecules in glioma cancer stem cells, the gliomas won’t grow in experimental systems. Therefore our aim is to design and test a drug that inhibits these molecules as a way of suppressing glioma cancer stem cells and treating glioma. Our approach to making a drug involves the use of the [REDACTED] supercomputer. A physicist on our team will use this computer and advanced computer programs to design chemicals that will bind to and inhibit a specific molecule in the glioma cancer stem cells. We will then make the chemicals and test them along with thousands of known chemicals. The tests will involve human glioma cells taken from brain cancer patients during surgery and grown in laboratory dishes. The chemical that is the most effective against the glioma cells, and which does not injure normal nervous system cells growing in laboratory dishes will be further developed as a drug for glioma that can be taken orally. This kind of cancer stem cell-based treatment would be completely new and has the potential for great benefit in brain cancer patients with fewer side effects than current chemotherapy and radiation therapy.
Statement of Benefit to California:
The proposed research will benefit the people of California in several important ways. Initially, the CIRM grant would benefit [REDACTED] in terms of grant revenue, helping [REDACTED] cover expenses and perhaps keep a number of people employed. Also, additional scientists and scientific technical personnel at more junior levels would be hired for this grant. Hence the proposed project would provide training for younger scientists and technicians and help prepare them for successful careers in Academia and Industry. The [REDACTED] and the California stem cell program would gain major national and international recognition if a successful brain cancer drug were to be developed from the proposed project. This would contribute to regaining respect and esteem for the state and [REDACTED], thereby encouraging outside investment, at a time when the State has suffered economically. [REDACTED] would largely own the patent rights to any drug developed by such a program, and if successful the drug could bring in moneys to the State via licensing or sublicensing to drug and healthcare companies worldwide. This revenue earning mechanism would be enormously amplified if the drug is effective in other stem cell driven cancers that express the target molecule including lung cancer, T-cell leukemia, melanoma and breast cancers. This often happens with successful anticancer drugs; initially they are targeted to a particular cancer and then are found to be useful in several cancers. One of our long term goals with developing a brain cancer therapeutic is to create a successful drug company based in [REDACTED]. Such a company would provide jobs for local residents, and would provide tax revenue for the State. The company would earn income directly through sales of the drug or via sales coupled with sub-licensing agreements. A large successful company of this nature based in California would attract national and international attention to the local Biotechnology business environment. Finally, a successful brain tumor treatment would profoundly benefit local California residents and suffering from this devastating illness. The majority of patients treated for brain tumors in California are California residents, and such a treatment would directly affect them and their families, friends and professional colleagues. If the drug proves to be active against lung, skin, breast or blood cancers the direct benefit in terms of medical treatment would be greatly expanded.
In this Development Candidate (DC) award application, the applicant aims to identify a small molecule transcription factor (TF) inhibitor as a lead therapeutic candidate for treatment of Glioblastoma Multiforme (GBM). The applicant proposes the TF as an appropriate therapeutic target as it is highly expressed in GBM cancer stem cells (CSCs); genetic silencing of this TF inhibits GBM growth in murine models; and the TF is expressed only at low levels in normal brain tissue and is not expressed in tissues outside the CNS. The applicant plans to screen for lead therapeutic candidates and conduct lead optimization and selection. In Aim 1, the applicant will perform high throughput screening (HTS) to identify hits that inhibit the TF. An existing compound library will be used for the screen and will be augmented with compounds identified through a computer-modeling screen. Also as a part of Aim 1, a GBM CSC assay will be developed and a reference standard for TF inhibition will be established. In Aim 2, hit compounds will be validated using the cell-based assay, and the best candidates will undergo chemical modification to optimize the lead candidates. In Aim 3, optimized lead candidates will be tested in vivo using human GBM mouse models and a single lead candidate will be selected. Reviewers agreed that identifying a drug that improves the survival of glioblastoma patients would make a major medical impact. However, the rationale in selecting this particular TF as a target for therapeutic intervention was questioned. First, the applicant does not provide convincing data that the knockdown of this TF results in decreased survival of GBM cells. Although published literature is referenced, the reviewers would have appreciated preliminary data demonstrating survival of primary GBM cells following TF inhibition. Additionally, reviewers noted that the applicant did not address critical safety issues related to the therapeutic target choice. The proposed target TF is expressed in oligodendrocyte progenitors in the normal brain and the applicant does not sufficiently address this potential toxicity issue or mechanisms by which the GBM cells might be distinguished from normal progenitor cells. Further, suppression of this TF is known to inhibit myelination, a process that is needed following radiation treatment. Given these concerns, reviewers were unconvinced by the rationale of target choice and did not think a lead compound targeting this TF would strongly impact the treatment of GBM patients. The feasibility and design of the experimental approach was deemed adequate. Reviewers appreciated the use of primary GBM patient-derived materials and the development of the RNAi TF reference standard and the dual approach to identifying inhibitor compounds. However, it was noted that the applicant did not address several issues and pitfalls. For Aim1, successful identification of hits depends on a validated and robust screening assay. That assay has not yet been developed and the protein components for the assay have not been produced. Moreover, the applicant does not provide important technical details concerning the screening assay. Reviewers also noted that the GBM CSC assay does not appear to be CSC focused but rather targets the global GBM response, thus diminishing the stem cell relatedness of the proposed project. Reviewers raised concern that the proposed neural progenitor cell (NPC) cytotoxicity assays do not sufficiently address potential toxicity to normal NPCs. In particular, potential oligodendrocyte progenitor toxicities were not discussed adequately. The proposal does not address the difficulty in differentiating NPCs to all three lineages and no details are provided on how this will be achieved. Reviewers also noted that the applicant does not sufficiently address potential concerns regarding the ability of the inhibitor to cross the blood-brain barrier (BBB) and tumor vasculature. Concerns were also raised regarding the completeness of activities and the overall timeline. Importantly there is no consideration of formulation, dose response, or therapeutic index of the selected compounds. Given that the screening experiments alone could take years, and the lack of any prototype molecules, reviewers were skeptical whether identification of a single lead compound is achievable in the proposed timeline. Reviewers viewed the principal investigator (PI) as a solid scientist with a strong track record in GBM, and the research team as a highly qualified group to pursue the major goals of the proposal. However, reviewers expressed concern that the PI’s team is too small to undertake a project of the scope and thought the project would benefit from additional collaborations. The resources and the environment were judged to be suitable for conducting the proposed research plan. In summary, this is a proposal to develop a lead small molecule TF inhibitor as a lead therapeutic candidate for treatment of GBM. Strengths of the proposal included its focus on an important unmet medical need and the experience of the applicant in the GBM field. Weaknesses include a number of significant problems with the rationale, experimental design and safety concerns, greatly diminishing the feasibility of the proposed approach.