Medulloblastoma is the most common malignant brain tumor in children, and a major cause of pediatric cancer deaths. Research on medulloblastoma has uncovered the driving force behind cancer growth for a large proportion of these tumors. In about one third of medulloblastoma cases, a set of molecular signals called the “Hedgehog pathway” controls growth of the cancer stem cell, which is responsible for tumor propagation and resistance. Current treatment strategies to block the Hedgehog pathway are very promising, but resistance to the currently employed drugs develops quickly. We propose a clinical trial designed to target the Hedgehog pathway in medulloblastoma using a newly discovered inhibitor of Hedgehog pathway activity that should circumvent the problem of drug resistance. The Hedgehog pathway is like a key in a lock that opens the door to cancer stem cell growth. The current treatment strategy to treat this disease secures the lock, but the tumor cell often manages to pick the lock. Our proposed strategy secures the lock, and also wedges a stopper behind the door.
Medulloblastoma is an important disease afflicting children. The Hedgehog pathway is critical in not only medulloblastoma, but also a number of other cancers, including certain types of lung, prostate, skin, bladder and colon cancers. Establishing an effective clinical strategy to inhibit Hedgehog pathway activity in medulloblastoma will pave the way for treatment of many thousands of people suffering from multiple forms of cancer.
Statement of Benefit to California:
Medulloblastoma, the most common malignant pediatric brain tumor, represents a significant health issue in children in California. The cost of treating just those children afflicted in California alone exceeds $50 million each year. In this proposal, we test a novel strategy to target a specific molecular cascade, the “Hedgehog pathway”, in the medulloblastoma cancer stem cell. Hedgehog pathway is known to be critical in the growth of approximately one third of medulloblastoma tumors, as well as in a number of other common human cancers. Successful completion of the proposed clinical trial will lead to improved outcomes in children with medulloblastoma, to healthier children in California, and to reduced medical and opportunity costs for the state. As a successful clinical strategy to target the Hedgehog pathway is relevant to many forms of lung, prostate, colon, skin and bladder cancer, this study will also pave the way for improved cancer therapy for thousands of Californians.
Medulloblastoma is the most common malignant pediatric brain tumor and a major cause of cancer deaths in children. While some treatments are available, these treatments are not satisfactory as they can have permanent neurologic consequences and tumor recurrence remains around 30% with a poor prognosis following recurrence. In a subset of medulloblastomas (Hh-subtype), the growth and persistence of the tumor has been suggested to depend on the hedgehog signaling pathway. The pathway has been suggested to drive proliferation of medulloblastoma cancer stem cells and be involved with recurrence of the tumor. Consequently, the applicant proposes a potential therapeutic candidate targeting the hedgehog pathway and hypothesizes that it can be used to treat patients with the disease. The applicant proposes to file an Investigation New Drug (IND) application with the Food and Drug Administration (FDA) and test clinically in a phase I/II trial whether the proposed therapeutic in combination with another approved drug can improve survival of patients with recurring Hh-subtype medulloblastoma.
Significance and Impact
- The therapeutic targets a well-described patient population with a significant unmet medical need.
- The proposal describes a modestly innovative but competitive approach and a worthwhile drug target, and the proposed therapeutic, if successfully developed, could offer a significant advantage in treatment of this disease. Thus, the impact of this proposal is potentially high.
- The applicants propose a single development candidate that meets the readiness criteria and the proposal states it will target medulloblastoma cancer stem cells. However, the cancer stem cell association of this proposal is weak as there is little evidence that this is the mechanism of action of the proposed therapy.
- The Target Product Profile (TPP) provided is achievable.
Project Rationale and Feasibility
- The applicants provide a strong rationale for the approach of using combined treatment to target the hedgehog pathway in medulloblastoma.
- The preclinical data are weak as there are no in vitro or in vivo preclinical studies with the combined therapy.
- The application did not include in vivo data demonstrating improved efficacy through combined treatment verses each drug alone.
- The preliminary data on toxicity do not address the toxicities of the drugs used in combination nor consider that use of the combination might result in a novel toxicity.
- In considering the dosing scheme, reviewers noted both a safety concern regarding the potential for toxicities in the target patient population and a feasibility concern regarding the ability of the applicant to identify a dose range that is both safe and efficacious.
- The IND-enabling studies are focused and will provide data necessary for an IND, however, not all IND-enabling studies and activities are adequately addressed. There is a need for additional efficacy and safety studies, particularly toxicity studies, using the combined treatment approach, and the applicants do not detail such experiments in the research plan.
- The preliminary in vitro data supports the use of the potential therapeutic in treatment of medulloblastoma.
- Both proposed drugs have been tested in the clinic and are FDA approved. This supports the ability of the applicant to complete the IND filing and the proposed clinical trial in 4 years.
- The draft plan for the clinical trial is straightforward, the proposed enrollment plan is reasonable, and the number of clinical centers involved is a strong point of the clinical plan.
Principal Investigator (PI) and Planning Leader
- The PI is a recognized leader in the field and an established translational investigator with a solid publication record.
- The PI is well trained and appropriately trained for carrying out the studies proposed in this application.
- The PI has extensive experience in leading clinical trials for children with brain tumors. The leadership of the PI is a strength of the proposal.
- A biosketch for the Planning Leader (PL) was not provided; however, the PL appears to be relatively junior and does not appear to have the appropriate expertise or experience to act in this capacity. The lack of completeness of the IND-enabling study plan might reflect this apparent lack of experience.