New Faculty II
Glioblastoma multiforme (GBM) is an aggressive, highly malignant type of brain tumor that resists all treatments developed and is highly lethal. Almost all patients with GBM die within one year after diagnosis. The proposed research seeks to develop a novel therapeutic approach to treating GBM and perhaps other malignant brain tumors by targeting particular types of stem cells that are believed to generate and/or repopulate tumors. Currently, there is no cure for GBM, and the prognosis is grim. Some patients respond differently to current common treatments for brain tumors, including chemotherapy and radiation therapy. However, the tumor virtually always grows back, even after complete surgical resection. Recent studies suggest that the reason may be that cancer stem cells (CSC) remain scattered in the brain, and are capable of completely repopulating the tumor even after treatments and surgical excision. The experiments proposed in this application may provide answers to these problems, and seek to address the basic mechanisms of cancer stem cells, how they respond to treatment, and how they might be targeted for destruction using the body’s natural defenses. In our proposed studies, we will first determine information about how CSC respond to chemotherapy in cell culture conditions. Next, we will determine how implanted tumors in mice respond to those same drugs, and evaluate proportions of CSC at baseline, and after treatment. We believe drug treatments will increase the number of CSC, because the drugs will preferentially kill non-CSC tumor cells, and therefore leave behind an enriched population of CSC that are highly resistant to treatment. Next we will directly manipulate the proportion of CSC in implanted tumors in mice. We will treat these mice with a vaccine therapy we have been developing that uses the tumor tissue to activate the immune system. Specifically, we take tumor tissue and treat dendritic cells (DCs) with that tumor tissue. DCs then activate cytotoxic T cells that kill tumor cells. However, thus far our vaccine has only shown limited success; we believe the reason is because CSC resist this therapy also. Therefore, we will attempt to more precisely target CSC by activating the immune system with dead CSC material. We will vary the proportion of CSC in the tumor material that we use to treat DCs with. Then we will test how effective this is in mice that have implanted tumors where we again control the proportion of CSC. If this proves only partially successful, we may attempt to combine vaccination treatment with chemotherapy, in the hopes that both treatments together can overwhelm the CSC and eradicate the tumors entirely. If successful, we may generate an entirely new way to treat GBM, and possibly one day other types of brain tumors also.
Statement of Benefit to California:
The 2006 Central Brain Tumor Registry of the United States reported that the incidence rate in the state of California for primary malignant brain tumors and other CNS tumors is approximately 6 per 100,000 California residents every year. Malignant brain tumors like glioblastoma multiforme (GBM) have a devastating prognosis, and no cure or effective treatment has been developed to date. Recent studies suggest that GBM brain tumors may be derived from cancer stem cells (CSC), and that these CSC are resistant to common therapies including chemotherapy and radiation therapy. Cancer stem cells are thought to be responsible for tumor recurrence after therapy, and that could be a reason why treatments are ineffective. We propose that targeting these cancer stem cells using immunologic ways to destroy them may consititute a new way to treat GBM, and/or may improve the efficacy of current therapies. The proposed research will test that notion. Our research will provide novel information regarding the function of CSC and could generate an entirely new way to treat GBM. The research proposed in this application will benefit the people of California by potentially identifying a novel way of treating brain tumors, which will have a direct benefit for the patient and their families, and could also lower the financial burden associated with this devastating disease.
This proposal is focused on the role of cancer stem cells (CSCs) in the malignant brain cancer, glioblastoma multiforme (GBM). In particular, the project is focused on assessing the sensitivity of glioma CSCs to chemotherapy and on developing an effective immunotherapy to GBM. The first aim is to evaluate the chemoresistance of a model glioblastoma cell line in culture. The second objective is to analyze chemosensitivity of CSCs and other tumor cells in a mouse model system. The third goal is to test approaches for priming dendritic cells to kill tumor cells and CSCs. Findings from these investigations could underlie new approaches for the treatment of brain tumors and other cancers. This proposal concerns an important and significant problem: the treatment of a highly aggressive cancer for which current therapies are ineffective. However, reviewers were unenthusiastic about the application because of serious deficiencies in the research plan. The rationale for several proposed experiments was unclear and key assumptions were unsubstantiated. The appropriateness of the use of the proposed glioblastoma cell line was not established. Additionally, it was unclear that appropriate cell markers were identified for distinguishing or purifying a homogeneous population of CSCs, and alternative approaches involving a CSC-specific signaling pathway were obscure. Reviewers had particular concerns with the rationale and prediction of results for the experiments focused on priming of dendritic cells in the last aim. The applicant has research experience with neural stem cells. Reviewers expressed concern about the applicant’s independence: his/her salary and lab space are provided by another researcher (who is also a named mentor). The applicant has published several papers with relevance to the proposed research, but the overall publication record is modest, and the applicant has yet to serve as senior author on a publication. The institutional facilities and resources available for the proposed research are excellent. Although the institutional letter indicated strong support for the applicant, reviewer enthusiasm for this application was decreased by the statement that institutional commitment to lab and office space was contingent on the applicant’s receiving the CIRM award.