Proposals test potentially transformative ideas that do not have extensive preliminary data but articulate a clear hypothesis and translational goals. Resources for such "high-risk, high-reward" projects are important to establish proof-of-concept, which may then leverage additional funding through more traditional avenues.
Next generation inhibitors against wild-type and mutant BRAF dimers
MRA Pilot Award
Evripidis Gavathiotis, Ph.D., Albert Einstein College of Medicine
More than 70 thousand people are diagnosed with melanoma skin cancer and more than 10 thousand die from the disease every year in the US. In 50% of melanoma cases, the protein kinase BRAF is mutated while in most of the remaining 50% of cases the BRAF is non-mutated but active. Each non-mutated BRAF molecule requires interaction with a similar partner molecule (dimerization) to remain active and oncogenic, in contrast to mutated BRAF which is very active without any partner (monomers). Intense medical research in recent years has succeeded to produce FDA approved drugs that target effectively mutated monomeric BRAF eliciting remarkable clinical responses. However, the activated non-mutated dimer BRAF remains poorly targeted, a fact that leads to resistance to current melanoma treatments and cancer relapse within a few months. This pilot project addresses this currently unmet medical problem. We propose to use our expertise in drug design, and our novel insights into BRAF structure and regulation, to create a battery of chemical compounds that will form the basis for next-generation melanoma drugs, which will specifically target activated dimer BRAFs.
MDSC recruitment as an adaptive resistance mechanism to PD-1 antibody therapy
MRA Pilot Award
Brent A. Hanks, M.D., Ph.D., Duke University Medical Center
While significant strides have been made in the development of agents that utilize the immune system to treat melanoma, many patients remain resistant to these treatment modalities. Selecting which patients will respond most favorably to this treatment approach and determining when melanomas are becoming resistant to ongoing immunotherapy remain important research goals for the field of melanoma. In order to reach these goals, the underlying mechanisms that melanomas develop to progress through active immunotherapy must be understood. Using a genetic mouse model that closely imitates human melanoma, we have determined that escape from anti-PD-1 antibody checkpoint immunotherapy is associated with the recruitment of an immune suppressive cell population known as the myeloid-derived suppressor cells. Using pre-clinical models of melanoma as well as specimens derived from advanced melanoma patients, we aim to characterize the underlying mechanism driving the recruitment of myeloid-derived suppressor cells in response to anti-PD-1 antibody therapy and to understand the role that this process plays in the development of immunotherapy resistance. Further work will investigate how the reversal of myeloid-derived suppressor cell recruitment is capable of augmenting the efficacy of anti-PD-1 antibody immunotherapy in melanoma.
Targeting Foxp3 and NMD blockade in melanoma to unleash tumor immunity
MRA Pilot Award
Fernando Pastor, Ph.D., Foundation for Applied Medical Research
The recent clinical advances in the treatment of advanced solid tumors, such as melanoma, have underscored the real potential of cancer immunotherapy. There is accumulated evidence that suggests that generation of effective antitumor immune responses requires the elimination of tumor-induced immunosuppression and a certain grade of tumor antigenicity. Tumors that are too similar to normal tissue from the antigenic point of view would hardly be recognized by the immune system as a possible foreign threat that needs to be rejected, escaping immune surveillance. Besides, tumors develop active mechanisms of immunosuppression. Therefore, it is reasonable to think that strategies that are aimed at solving only one of these problems would have a limited success. In order to have a broader therapeutic benefit, it is important to conceive novel approaches that would allow both the enhancement of tumor antigenicity and counteracting tumor immunosuppression. Here we propose a combination of two pioneer clinically feasible therapeutic strategies based on aptamer technology to achieve that goal. We anticipate that results of the proposed studies are likely to bring tumor-cell targeting into clinical application for immunotherapy of melanoma, and potentially other solid tumors. In the long-term perspective, this work can generate novel, more effective and safer therapeutics, expanding treatment options for the benefit of melanoma patients.
Dissecting the significance of pigment heterogeneity in cutaneous melanoma
MRA Pilot Award
Mark James Shackleton, M.B.B.S., Ph.D., The University of Melbourne
Many cancers, including melanomas, contain cancer cells that appear different from one another, even though they all grow from the same original cell. Understanding how this happens is important as the same processes that cause cancer cells to become different from one another also enable cancers to spread to different parts of the body and to become resistant to therapies. We have developed a novel method for separating from the same melanoma cells that are different according to whether or not they produce a pigment called melanin, which is what gives our skin and hair its colour and is also found in most melanomas. Unexpectedly, we found that patient melanoma cells that contain melanin are less able to promote the growth of melanomas than cells without melanin, even though those cells are present within the same melanomas. This discovery allows for the first time an unbiased and detailed investigation, enabled by funds from this grant, of the molecular changes that promote or inhibit melanoma cell growth. The results of the project will deepen our understanding of how melanoma grow and spread, and thereby identify new opportunities to stop these happening.
A novel T cell regulatory receptor as a target for cancer therapy
MRA Pilot Award
Li Wang, Ph.D., The Medical College of Wisconsin, Inc.
Immunotherapy utilizes body’s own immune system to fight against cancer, by generating cytotoxic T cells that directly kill tumor cells. Among the approaches that boost tumor-specific T cell responses, antibodies that block immune-checkpoint proteins such as CTLA-4 and PD-1 have become breakthrough therapies for late-stage melanoma patients. Alternatively, agonistic mAb targeting T cell costimulatory receptors such as OX40 and 4-1BB (CD137) have shown promising results. Despite the promising outcomes in the clinic, significant percentages of patients still failed to respond to these treatments. Alternative therapeutic strategies are continuously being sought after. Our current work has identified a novel Ig domain-containing receptor that plays a key role in regulating T cell activation. In this pilot application, we propose to investigate the role of this T cell regulatory receptor in regulating the anti-tumor T cell immunity. We will also develop novel agents that target this receptor, and determine if these agents will suppress tumor growth in preclinical melanoma models. The completion of this pilot study will build a foundation for developing therapeutic agents that target this novel T cell regulatory molecule for the treatment of human cancer, particularly melanoma.
Inhibitors of B-Raf through the dimerization interface
MRA Pilot Award
Campbell McInnes, Ph.D., University of South Carolina
In recent years, new targeted drugs have been developed which initially were thought to be transformative in the treatment of metastatic melanoma. These new agents include the drug vemurafenib and were designed to block the activity of a protein which is found only in the tumors and frequently is the underlying cause of this type of skin cancer. Despite dramatic initial responses from the majority of treated individuals (where tumors shrunk and in many cases disappeared altogether), resistance to these targeted agents quickly emerged and patients relapsed in many cases even worse than before treatment. Further studies revealed that the cause of such resistance results from the melanoma becoming dependent on what is called “paradoxical signaling”. This occurs when instead of the drug inhibiting the mutant protein, it is instead activates it by binding to a different form of the protein which then stimulates its activity thereby having the opposite effect. As a consequence, the growth of the tumor is increased as time progresses and therefore leads to the resistance to treatments. The scientific team involved in this proposal have discovered a new way of interfering with this paradoxical signaling that involves the use of smaller segments of the protein drug target. “Peptide inhibitors” based on these smaller segments have been shown to block paradoxical signaling and therefore have promise for development as a new class of drugs that might treat patients resistant to current treatments and which might be used in combination with vemurafenib and other similar agents. In this application, we propose to carry out a detailed investigation of how these “proteomimetics” function in blocking paradoxical signaling with the aim of improving their effectiveness and making such compounds more like molecules that can be developed as anti-melanoma therapeutics.
Anoikis effector as driver and drug target in metastatic melanoma
MRA Pilot Award
Narendra Wajapeyee, Ph.D., Yale University
Melanoma accounts for more than 10,000 deaths annually in the United States. A large majority of deaths due to melanoma occurs because of its spread (also known as metastasis) to other organs of the body, such as lung and brain. Therefore, it is expected that better understanding of melanoma metastasis will provide new opportunities to prevent and effectively treat metastatic melanoma. One of the important steps for a melanoma cells to undergo metastatic progression is the acquisition of the ability to survive in blood stream and reach and colonize distal organs, such as lung and brain, and form metastases. This occurs due to a change in melanoma cells that is referred to as development of anoikis resistance. Therefore, we aimed to identify factors that are responsible for anoikis resistance in metastatic melanoma cells and allow them to form metastasis. The idea was that once such factors are identified, these can then be targeted to effectively treat metastastic melanoma. Towards this goal, we used an experimental approach of RNA interference screening. Specifically, we targeted 1500 human genes that encodes for proteins for which drugs are available, many of which are in clinic. Using this approach, we identified Maternal Embryonic Leucine Zipper Kinase (MELK) as a factor that causes anoikis resistance in metastatic melanoma cells. Strikingly, we find that MELK is highly overexpressed in patient samples of metastatic melanoma and its overexpression associates with high likelyhood to develop metastasis. Based on these results, the overall goal of this project is to determine the role and mechanism of MELK as a driver of melanoma metastasis and test if blocking MELK using pharmacological drugs can be used as a novel theapy for treating metastatic melanoma. In sum, we will validate MELK as novel factor that promote melanoma metastasis and validate MELK inhibitory drugs for treating highly aggressive and difficult to treat metastatic melanoma.
A novel mechanism of melanoma immunotherapy resistance
Society for Immunotherapy of Cancer-MRA Pilot Award
Bin Zhang, M.D., Ph.D., Northwestern University
Malignant melanoma is characterized by a rapid progression, metastasis to regional lymph nodes and distant organs, and often resistance to chemotherapy and radiotherapy. According to the National Cancer Institute, it is estimated that 76,100 Americans will be newly diagnosed with melanoma and about 9,710 patients will die of the disease. Recent approval of YERVOY™ (ipilimumab, anti-CTLA-4) and Keytruda (pembrolizumab, anti-PD-1) by the US FDA marks the validation of immunotherapy for advanced metastatic melanoma patients, which has led to a renaissance in melanoma therapeutics using immunostimulatory monoclonal antibodies (mAbs) that enhance immune responses. These agents are including antagonists of immune-repressor molecules (e.g. CTLA-4 and PD-1) or agonists of immune-activating receptors (e.g. CD137, OX40 and CD40). Unfortunately, therapeutic benefit has been limited to a fraction of patients. This present project is searching for the resistance mechanisms underlying responsiveness to agonist mAbs directed against costimulatory molecule OX40 and development of novel combinatorial strategies. We have proposed an inhibitory role of a critical ecto-enzyme CD73 in the context of immunotherapies targeting immune costimulatory molecules. We hope to rapidly translate this knowledge into new combinatorial strategies using CD73 blockade for improving melanoma immunotherapy.
RADVAX: stereotactic body radiation therapy with ipilimumab in melanoma
MRA Pilot Award
Ramesh Rengan, M.D., Ph.D., University of Washington
A landmark trial recently demonstrated that the immunosimulatory drug, ipilimumab, significantly improves survival in patients with metastatic melanoma. This was the first trial to show an improvement in survival in metastatic melanoma where prognosis is usually poor. This improvement was seen despite only 10% of patients responded to the drug. Ipilimumab works by blocking CTLA-4, a molecule that is responsible for 'braking' the immune response once it is activated. However, in order for ipilimumab to work the patient's immune system has to be activated against melanoma before the drug is given. If an anti-melanoma immune response is not present, ipilimumab is ineffective as there is nothing to 'brake'. Our group believes that the reason why the patients do not respond to the drug is that their immune system has not yet been activated against the disease. There is evidence that radiation, when delivered using high doses per treatment (known as SBRT), can stimulate an anti-tumor immune response by forcing the radiated tumor to release antigens which then activate the immune system. Our proposal is to treat patients with metastatic melanoma with SBRT to a single focus of tumor in order to activate the immune response and then administer ipilimumab to these patients. We believe that this approach will increase the percentage of patients who will respond to ipilimumab by stimulating a melanoma-specific immune response in these patients. This proposal aims to test the safety feasibility of this combined approach in an attempt to improve outcomes in this disease.
Discovery of genes for melanoma development using a powerful new approach
MRA Pilot Award
Graeme Walker, Ph.D., Queensland Institute of Medical Research
The incidence of melanoma is rising worldwide. Once it spreads beyond the skin, this cancer is notoriously difficult to treat, hence new treatments are needed to stop this deadly disease. Sun exposure is a major risk factor in melanoma development, but genetic background is also important. We will find genes that determine our susceptibility to melanoma, some of which may protect against the neoplasm, by using two unique and world-leading resources. The first is a mouse model of mole (a melanoma precursor lesion) and melanoma development. The second is a large and innovative resource of genetically-defined mouse strains, designed to provide a powerful means of mapping genes for complex diseases (i.e. where more than one gene may be involved). Never before have such mouse systems been available to study the genetics of melanoma. By studying melanoma in these mouse strains we will determine which genes protect against the development of moles and melanoma. The discovery of such genes will help researchers better understand the causes of melanoma, and how they grow and evade the immune system. These genes encode proteins that can be targeted to provide opportunities to find new treatments.
Repurposing anthrax toxin for imaging and treatment of melanoma
MRA Pilot Award (Anonymous Donor)
Kenneth Bradley, Ph.D.,University of California, Los Angeles
Malignant melanoma is the most deadly skin cancer, and once it metastasizes to distal sites, it is almost always lethal and currently considered incurable. Much like botulinum neurotoxin has been successfully repurposed for medical and cosmetic use as BOTOX, other bacterial toxins have been used to treat various cancers. Indeed, anthrax toxin has been proposed as a novel treatment for malignant melanoma because it blocks cellular processes required for the tumor to grow. However, the key to success is to ensure that the toxin affects only the problematic cells. In the case of BOTOX, clinicians restrict the toxin activity by injecting only at the site to be treated. However, directed delivery is not feasible for metastatic melanoma. We propose to achieve the same goal of directed delivery for anthrax toxin through genetic engineering. We have generated forms of anthrax toxin that are molecularly targeted to interact preferentially with tumors. Here we will test these engineered toxins for their ability to treat melanoma and also to serve as markers to detect metastases.
Epigenetic differentiation therapy for melanoma
MRA Collaborative Donor Pilot Award
Eva Hernando, Ph.D., New York University School of Medicine
Melanoma aggressiveness has been attributed to a core of therapeutically resistant cells within these tumors, which are likely responsible for their ability to reach other organs and recur after surgery. Remarkably, these cells display genetic features characteristic of pluripotent stem cells. We propose to develop small chemical inhibitors that interfere with melanoma stem cell properties as a novel therapeutic approach against these tumors. Preliminary results from our laboratory indicate that a new class of compounds, which control access of some factors to chromatin, reduce the expression of genes required for stem cell maintenance and impair melanoma cell growth. We propose to study the effects of three small chemical inhibitors in a large panel of established melanoma cell lines and short-term cultures derived from fresh tissue specimens. First, we will assess the antitumoral effects of these compounds in cells cultured in vitro, and then select the most promising one for preclinical testing in mice and chemical optimization. Moreover, we will dissect the mechanism of action of these new inhibitors, with the goal of determining which patients could clinically benefit from this novel therapeutic strategy.
In vitro and in vivo models for the study of KIT-activated melanoma
MRA Pilot Award
Brian Rubin, M.D., Ph.D., Cleveland Clinic Foundation
Along with other scientists, we recently discovered that a group of melanomas, an important human cancer that is increasing in numbers, contain genetic mutations that activate a protein known as KIT. KIT is critical to the function of these melanomas. KIT mutations in melanoma were discovered by looking for KIT mutations in human melanoma tissues. However, to further study how KIT functions to cause melanomas, it is necessary to develop live cell-based models and animal models. It is the major purpose of this proposal to develop and study both live cell-based models and two different types of mouse models. Together these models will give us the tools to study how KIT is involved in tumor formation and the progression from benign nevus to malignant melanoma. These models will also allow us to evaluate newly developed therapies. This is important because the more thoroughly that we are able to study KIT-activated melanoma in model systems and evaluate potential therapies, the more rapidly and confidently we can move these therapies into humans for treatment.
^ Back to Top
Sulforaphane, a melanoma prevention agent for high-risk MC1R genotypes
MRA Pilot Award
Sancy Leachman, University of Utah
Sulforaphane (SF), a compound derived from broccoli sprouts, has the potential to compensate for the defective response to ultraviolet light that underlies the increased risk for melanoma suffered by individuals with mutations in MC1R (associated with fair skin and red hair). Leachman's laboratory conducted studies to evaluate if this agent merits advancement to a clinical trial for prevention of melanoma in this high-risk population. Using cultured human melanocytes and human skin samples, they found that SF improved the antioxidant response and increased pigment production after UV exposure. These promising results provide a basis for additional studies to design a new melanoma prevention strategy for persons with genetic pre-disposition for melanoma, specifically with red hair and inability to tan.
Mechanisms of melanoma treatment resistance
MRA Pilot Award
Maria Wei, North California Institute for Research and Education, University of California San Francisco
Melanoma is an aggressive cancer of the skin and eyes that has a high tendency towards metastatic behavior. The incidence of this malignancy is rising, in marked contrast to the declining incidence of other, more common cancers. There has been no breakthrough development in melanoma therapeutics for more than 25 years, and currently there is no effective treatment for metastatic disease. Recent studies from this laboratory have demonstrated that melanoma sensitivity to chemotherapy treatment is influenced by a pathway that regulates the formation of a compartment found in melanomas, called melanosomes. Normally, the pigment melanin (which gives rise to the color found in the skin, eyes and hair) is synthesized and stored within melanosomes and then (in the skin) is secreted, and taken up by neighboring cells called keratinocytes. Wei found that mutations in genes resulting in aberrant melanosome formation also cause increased melanoma sensitivity to a variety of chemotherapy agents, suggesting that melanosomes may play a fundamental role in melanoma chemosensitivity. In these proposed studies, Wei will investigate what role these genes, known to regulate melanosomes, play in chemotherapy resistance and how they could be targeted for the development of novel melanoma therapies.
Treatment of established melanoma by tumor-specific Th17 cells
MRA Pilot Award
Xue-Zhong Yu, Moffitt Cancer Center
Tumor-specific CD8+ cytotoxic T lymphocytes have been the focus for the lymphocyte-based cancer immunotherapy; however the complete tumor regression has been achieved in only a minority of melanoma patients. Recent evidence indicates that CD4 T cells may be a determining factor in promoting or inhibiting anti-tumor responses through T helper cells or regulatory T cells, respectively. Yu's laboratory as well as others discovered that Th17 cells, a newly defined T helper subset, are highly effective in eradicating tumors once they are directed to tumor associated antigens. Yu will further study the potential of Th17 cells in cancer immunotherapy in the combination of myeloabliative bone marrow transplantation. The proposed strategy utilizes the advantages of host lymphocyte depletion, hematopoietic stem cells, and redirection of T cell specificity to endogenous melanoma-associated antigen. The proposed study is expected to establish a novel strategy to treat established melanoma in preclinical models that may be readily applicable in clinic.
^ Back to Top