Early Translational I
$3 122 404
In 2008, the American Cancer Society estimates that in this country alone approximately 8,420 deaths will occur from melanoma and another 62,480 cases of melanoma are expected to be diagnosed. For the most advanced cases of melanoma, called Stage IV metastatic melanoma, the five year survival rate is 8 percent. Only two FDA-approved treatment options exist, dacarbazine and interleukin-2, and they have little success in treating this disease. Other than dacarbazine, which was introduced in 1975, and interleukin-2, no new drugs have been successfully developed in part because the specific mechanism of action of melanoma metastases is unknown. However, recent scientific studies have identified possible clues as to how this disease evolves; suggesting certain biological targets in stem cell pathways are instrumental to the disease’s genesis and progression. This research has also revealed that known FDA-approved drugs for other indications act upon these stem cell pathways in such a way that melanoma cancer cells may be differentiated toward a more normal, less proliferative cell state. Finding FDA-approved drugs for other indications that also work in metastatic melanoma will speed drug development and clinical trials to provide a therapy to patients quickly. A recent clinical study of one of these FDA-approved drugs demonstrated efficacious effect in 40 percent of the melanoma patients, including an observation of complete suppression of the disease. We now need to translate these research discoveries and clinical observations to support the development of new therapeutic options for metastatic melanoma. This CIRM Translational Research grant will leverage and utilize these recent scientific discoveries in two ways: 1) by supplying resources to allow for our advanced technological approaches to better understand stem cells’ mechanistic role in this disease; and 2) to quickly identify and develop new IND-ready therapies for this disease by capitalizing on the identity of chemical classes of those FDA-approved drugs and other human experienced compounds identified in these previous studies. This CIRM supported grant will have the opportunity to discover and develop new medicines for a disease that will have an immediate, near term beneficial impact for California citizens.
Statement of Benefit to California:
Of the 62,480 cases of melanoma expected to be diagnosed this year, one in six will be in California. Approximately 20 Californians per week will die this year from melanoma. Estimates of melanoma treatment costs alone averages more than $740 million and may exceed $1 billion each year in the United States [REDACTED]. The treatment cost for California will approach $200 million. If other costs such as complication risks and economic workforce losses were factored into the analysis, the cost would be several times higher. Late-stage melanoma patients have the most expenses for treatment and have little therapeutic options. About 90 percent of the total annual direct costs for treating melanoma is spent on those with advanced disease. Finding a cure for metastatic melanoma would deliver direct life-saving benefits to thousands of patients and needed economic support to the state of California. Utilizing our advanced clinical approach and research in metastatic melanoma would also fulfill the CIRM mandate to deliver highly effective therapies based on stem cell biology within a short time frame to benefit the health of Californians and the world.
The overall goal of this proposal is to develop agents that eliminate melanoma cancer stem cells (CSC). Investigators will attempt determine whether a known FDA-approved drug achieves its effect by Wnt mediated differentiation of melanoma CSC. For these studies, the investigators will generate a series of 10 melanoma cell lines expressing a Wnt pathway sensitive reporter gene. A 30,000 compound library will then be screened with these reporter lines with the goal of identifying additional, more potent Wnt agonists. Hits from the screen will be narrowed down to 2-3 compounds based on in vivo growth and metastasis of human melanoma xenografts and enriched melanoma stem cells to the lung. In vitro and in vivo pharmacology and pharmacokinetics of the lead compounds will also be measured. A successful treatment for metastatic melanoma would have a large impact. The PI has a solid record in industry and is well suited to lead a translational program. The rest of the team also has strong credentials and resources and environment should be adequate to complete the proposed studies. However, this conceptually driven application represents an early stage project. Stronger preliminary data are required to support the specific aims. For example, the investigators do not provide data that the hits identified act on cancer stem cells or that they can drive differentiation of cancer stem cells via activation of Wnt. The plan assumes compounds that induce CSC differentiation can be identified with reporter cell lines, but no data are provided to validate this approach. Investigators plan to assess CSC in patient blood samples, but provide no data regarding the sensitivity of their CSC detection assay or their ability to detect CSC in blood samples or cell lines. Reservations were universal regarding the ability to meet the overly optimistic timelines for the amount of work proposed in the application. For example, screening 30000 compounds at 8 concentrations in 12 lines (10 of which are yet to be generated) is in itself a major effort, and a plan isn’t presented to prioritize potentially cell type specific hits. There are also some conceptual issues. A recent publication suggests cancer stem cell activity may be dependent upon host, rather than cell intrinsic, factors casting doubt upon the existence of this population. Wnt proteins have demonstrated cell type dependent, pleiotropic actions. In some stem cells, Wnt proteins can promote differentiation while in others they promote self-renewal, raising the possibility of potentially deleterious effects of compounds that modulate Wnt signaling. Concern was raised that this was inadequately addressed. This application addresses an unmet medical need and if successful the work could have great impact. Unfortunately, the dearth of feasibility data, overly ambitious timelines and conceptual issues left reviewers unenthusiastic about the program’s probability of success.