Commitment to Research

The Susan Fazio Foundation has made a major commitment to melanoma research since 2006 by funding research grants through the Melanoma Research Foundation.

Grants have been given to:

The Susan Fazio Foundation has also made a commitment to support Lynn Schuchter, M.D. and the Abramson Cancer Center at University of Pennsylvania by contributing $5,000 a year for 5 years. Your partnership with the Foundation will advance scientific investigation through this commitment to research.

like all cancers, mucosal melanomas demonstrate changes in their DNA, the blueprint of the cell

2014 – Comprehensive Genomic Characterization of Mucosal Melanoma

Mucosal melanoma is a rare sub-type of melanoma that arises within the mucosal membranes of the respiratory, gastrointestinal and urogenital tracts. Estimates of 5-year survival range from 15-40%, significantly lower than in cutaneous melanoma. The distinct genetic profile of mucosal melanomas may account for this difference in survival. Like all cancers, mucosal melanomas demonstrate changes in their DNA, the blueprint of the cell. DNA can be thought of as a long string of letters (over 3 billion) that is present within each of our cells. Changing individual letters (substitution), adding or subtracting letters (insertion/deletion), or breaking and rejoining the sequence of letters at different points (rearrangement) are all different types of mutations that can result in a faulty blueprint that causes uncontrolled growth and the spread of cancer.

Aside from the identification of BRAF, NRAS and KIT alterations in about one-quarter of mucosal melanomas, little is known about molecular drivers of the disease. Due to the relative rarity of mucosal melanoma, the genetic basis of the disease has not been comprehensively studied as only a few cases have been included in broader melanoma sequencing studies and previous cohorts focusing on mucosal melanoma were relatively small. Advancements in sequencing technologies have driven down costs per sample and improved our ability to sequence small quantities of DNA and RNA.

In combination with our increased understanding of the genomic landscape of melanoma and the development of targeted therapies, a focused study of the genetics of mucosal melanoma is poised to make a significant impact. At the University of California, San Francisco, we have a large archive of pathology specimens reaching back decades, which is an ideal resource for rare tumors, including mucosal melanomas. We will be performing multiple state-of-the-art genomic technologies on tissue blocks of primary mucosal melanomas to obtain DNA and RNA for sequencing analysis.

Our goal is to identify mutations that can be treated in all of the cases we analyze. We will start with the sequencing portions of the DNA methods most likely to contain targetable mutations. For those melanomas in which a targetable mutation is not identified, we will sequence additional portions of the DNA and use methods that are better at detecting rearrangements. This strategy is designed to make the best use of our resources to identify new opportunities for treatment.

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melanoma is responsible for over 77% of skin cancer deaths

2011-2013 – Evaluating c-KIT in Mucosal Melanoma

Melanoma is one of the most rapidly increasing malignancies worldwide. Although it accounts for only 4% of all skin cancers with over 65,000 new cases diagnosed annually in the United States, it is responsible for over 77% of skin cancer deaths. If detected early, the disease is easily treated surgically; however, once the disease has metastasized it is largely refractory to current therapies and is associated with high mortality. The four most common forms of melanoma are Superficial spreading, Nodular, Lentigo maligna and Acral lentiginous. Mucosal melanomas are categorized as Acral lentiginous melanomas and affect all races with similar frequency. Nearly a third of all newly diagnosed cases possess regional spread, and despite aggressive surgical intervention, result in significant metastatic dissemination to other organs, especially the liver, lungs, brain and intestines, which is associated with poor prognosis.

As we enter the era of targeted therapy, it is vital to classify tumors on the basis of their driving genetic alterations so that appropriate therapeutic agents can be developed. While the majority of cutaneous melanomas possess activating mutations in BRAF, alterations in a vital cell surface receptor c-KIT have been identified as the most common event in mucosal melanomas. Therefore, therapeutic targeting of c-KIT has recently gained interest. Although several phase II clinical trials with an inhibitor of c-KIT in unselected melanoma patients proved disappointing, recent reports highlight several dramatic responses in patients diagnosed with mucosal melanomas that possessed c-KIT alterations. This has led to expanded clinical evaluation of c-KIT inhibitors in stratified patient cohorts. Despite increasing interest in targeting c-KIT in mucosal melanomas, very little is known regarding a role for c-KIT in promoting melanoma initiation and progression. To this end we will evaluate a role for c-KIT alterations in promoting mucosal melanomas in concert with other implicated cooperating genomic alterations in our novel preclinical model. We will assess multiple c-KIT directed agents and address potential mechanisms of resistance. Importantly, our studies will provide insight into which c-KIT alterations and cooperating events are responsive to various c-KIT inhibitors and identify factors leading to drug resistance in order to develop better therapeutic strategies for treating mucosal melanoma.

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Dr. Vitali Alexeev

finding treatments to help melanoma patients who are truly in need of new therapies

2010 – Joe Fazio Visits Dr. Vitali Alexeev at Thomas Jefferson

I recently had the pleasure of visiting Dr. Vitali Alexeev in his laboratory at Thomas Jefferson University/Jefferson Medical College. Dr. Alexeev was the recipient of a 2009 Career Development Award, which was funded by the Susan Fazio Foundation. Dr. Alexeev’s research is focused on the study of highly conserved non-coding RNA molecules termed microRNA. More than 600 different microRNAs have been identified. However, the biological function of only a few microRNAs is known. Specifically, the objective of Dr. Alexeev’s studies is to advance the understanding of the role of microRNAs in melanoma and to determine if microRNA targeting could be used for melanoma treatment.

During the visit, Dr. Alexeev mentioned that he believes that combined therapies will work best in treating melanoma. This is a treatment program combining immunotherapy with molecular therapy which inhibits melanoma growth. Dr. Alexeev and his staff are involved with 1) design of small nucleic acid molecules to inhibit microRNA that facilitate melanoma growth, 2) development of novel protein and nucleic acid-based approaches that assist melanoma immunotherapy 4) testing of reagents on human and mouse melanoma cells, and 4) animal research aimed at the assessment of melanoma treatment efficacy.

Dr. Alexeev said that, unlike researchers in some other fields, melanoma researchers tend to cooperate with one another. In fact, Dr. Alexeev is collaborating with several researchers and clinicians who study melanoma and develop melanoma-specific treatments including Dr. Boris Bastian, the 2008 recipient of an Established Investigator Award, also funded by the Susan Fazio Foundation. Dr. Bastian is currently at the University of California, San Francisco.

What impressed me the most about Dr. Alexeev was that, during the visit, he continually mentioned the urgency of finding treatments to help melanoma patients who are truly in need of new therapies. While some researches may lose focus of the patient while concentrating on the many details of complicated research, Dr. Alexeev has a firm grasp on the real purpose of his studies. At the conclusion of the tour, Dr. Alexeev expressed his appreciation to the Susan Fazio Foundation for funding his research and indicated that his studies would not be possible without the support of the Susan Fazio Foundation.

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Dr. Vitali Alexeev

The long-term objective of our studies is to advance the understanding of the role of microRNAs in melanoma.

2009 – Dr. Vitali Alexeev

Studies of last decade demonstrated that in cutaneous melanomas harboring activating mutation in BRAF proto-oncogene, cKit receptor tyrosine kinase (RTK) is often down-modulated, and that re-expression and activation of this protein leads to the induction of programmed cell death (apoptosis) of malignant cells. On contrary, in mucosal and uveal melanomas, amplification of the c-kit gene coding for cKit RTK and activation of this receptor is frequently associated with malignant phenotype and tumorigenicity. Although such discrepancy is not well-understood, there is accumulating evidence that expression of cKit RTK in various tumors could be regulated by a new class of highly conserved non-coding RNA molecules termed as microRNA (miRNA). Up to date, more than 600 different miRNA species were identified. Moreover, studies on various human tumors showed that some of these molecules may act as oncogenes, while other — as tumor suppressor genes. However, the biological function of only a few miRNAs is known. Very limited and discrete information regarding miRNA expression and function in melanoma is currently available.

Our analysis of miRNA expression in melanomas and primary melanoma cell lines isolated from tumors on different stages of tumor progression showed an unusual up-regulation of several miRNA species including has-mir-221, and inverse correlation between expressions of this miRNA and c-kit gene. Our data also indicates that targeted, nucleic acid-based inhibition of has-mir-221 in cKit-negative cutaneous melanoma cells leads to the restoration of the cKit protein expression and cKit-dependent induction of apoptosis of malignant cells.

As has-mir-221 can potentially inhibit expression of several pivotal protein including cKit RTK, p27Kip-1 tumor suppressor gene, and MITF transcription factor, we hypothesized that up-regulation of has-mir-221 (and other miRNAs) is crucial in the tumorigenesis and advancement of cutaneous melanoma. We also suggested that supplementation of cKit-dependent melanomas with has-mir-221 and targeted, nucleic acid based inhibition of this miRNA in cKit-negative, BRAF-mutant tumors can be utilized for inhibition of melanoma progression. Therefore, the long-term objective of our studies is to advance the understanding of the role of microRNAs in melanoma. The primary goals of the current project are (1) to delineate the role of cKit-inhibiting microRNAs and cKit itself in the progression of different types of melanoma and (2) to test whether miRNA supplementation or inhibition is applicable for the targeted inhibition of melanoma.

Overall, the fulfillment of this project will allow delineating the role cKit and cKit-inhibiting miRNAs in different melanomas, identifying potential targets of these miRNA and testing whether miRNA targeting could be used for melanoma treatment. The results of these studies will form a platform for the translational research program aimed at the development of new modalities for melanoma therapy.

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Dr. Boris Bastian

Melanomas can vary significantly in their appearance.

2008 – Dr. Boris Bastian

Melanomas can vary significantly in their appearance, both how they appear on the skin and under the microscope, the body site in which they arise, and their relation to sun exposure. This has lead to the development of a melanoma classification, which distinguishes four main types: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), nodular melanoma (NM) and acral lentiginous melanoma (ALM). These distinctions are based on the observation that certain combinations of morphological features of the microscopic growth pattern of melanoma during its early progression phase are associated with clinical features such as anatomic site of the primary tumor, pace of tumor evolution, and patient age. However, distinguishing these subtypes has had minimal or no impact on management of patients with metastatic disease. A major reason is that no significant difference in overall survival or treatment responses could be demonstrated between the categories, when tumors of equivalent tumor thickness were compared or after metastasis had occurred. Over the last years a series of studies have provided strong genetic support for the existence of distinct melanoma types and have opened opportunities for specific therapeutic interventions targeted against some of the genetic alterations. What is currently not known is whether and how this new knowledge can be integrated into the existing classification system. Our preliminary data indicate strong correlations between genetic alterations in melanoma and histopathological and clinical features of the primary tumor. With the support of the Melanoma Research Foundation we have initiatef a concerted effort to integrate the emerging genetic information into the current melanoma classification with the overall goal to create melanoma subgroups that require the same clinical management because they are biologically related. In two workshops we had brought together experts in surgical, oncological, pathological, and epidemiologic aspect of melanoma and to develop a strategy for an integrated classification. With the funding provided with the MRF Established Investigator Award we are now validating our previously defined algorithm that uses simple microscopic features of the primary tumor to define a subgroup of melanoma that is highly enriched for BRAF mutations. This approach is expected to address the largest melanoma subgroup in the US and Europe. In this step we are particularly interested in determining: a) the robustness of the ability to use morphologic information to predict BRAF mutation status in an independent cohort; b) if melanomas with that these features also show differences in their clinical behavior such as pattern of metastasis, overall survival, or relapse-free survival; c) and whether the morphologic signature or BRAF mutation status better predict this clinical behavior. If e.g. the morphologic signature would be more predictive of clinical behavior independent of the presence of a BRAF mutation, this would support the importance of continuing to use morphologic features as a key component of a revised melanoma classification system. Such a finding could provide important genetic information and help identifying patients that need in a fit from therapies directed against BRAF. For example it is conceivable that melanomas that show a morphological “signature” of BRAF mutation without carrying the mutation itself, may harbor mutations in functionally closely related or equivalent genes (e.g. MEK). If this paradigm holds, a refined classification scheme could thus help with therapy stratification and guidance for the discovery of novel melanoma oncogenes within morphologically uniform subsets.

In our study we are using a cohort of 384 primary invasive melanomas. The cohort is enriched for higher-risk primaries with tumor thicknesses greater than 1 mm and clinical follow-up information is available for all cases and represents the most common melanoma types in the United States and Europe. Eleven expert pathologists from the US, Europe, and Australia have scored the previously agreed-upon morphological features. The reproducibility of the morphological criteria has been shown to be very good. We have determined the mutation status of BRAF and NRAS from DNA extracted from the tumor cells. We are now testing the sensitivity, specificity and accuracy of the previously defined algorithm. If we succeed in replicating our definition of a subgroup of melanoma, which is highly enriched in BRAF mutations this would represent a significant step forward in building a refined classification scheme, as this group of melanomas is expected to account for the majority of melanomas in the United States.

The second goal of our study is to determine whether the remainder of melanomas can be segregated into additional subgroups that share genetic alterations and morphologic or clinical features. For this purpose we will analyze other genes frequently mutated in melanoma using the same cohort of cases and determine whether any of the genes show similar association with clinicopathological features as BRAF. Such a finding would indicate the presence of additional biologically relevant subgroups that would have to be confirmed using additional cohort of melanomas as a future step. The work of this study will be carried out in close collaboration and consultation with the melanoma experts that were involved with the design of the study to ensure rapid clinical implementation emerging from this work. For this purpose the group will come together for another meeting after completion of the first phase of the project to discuss the progress and detailed course of the second phase of the study.

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Dr. Arati Sharma

Malignant melanoma is the seventh most common cancer in the US.

2007 – Dr. Arati Sharma

Malignant melanoma is the seventh most common cancer in the US, affecting 1 in 64 Americans and predicted to affect 1 in 15 US citizens by 2010. The incidence increases approximately 4% each year, giving this cancer the second fastest growth rate in the US. Statistically, one American dies from melanoma every hour. Currently, the major therapeutic strategy for melanoma involves early detection and surgical removal. Despite these preventive strategies and increased use of sunscreen, incidence and mortality rates of melanoma continues to rise in the US and worldwide with no effective long-term treatment exists to target the proteins that trigger melanoma.

We have developed drugs from naturally occurring compounds that can inhibit the growth of melanoma tumors in mice by ~ 60 percent with a very low dose. We have previously showed the therapeutic potential of targeting the Akt3 protein in inhibiting the development of melanoma. The search for a drug to block the protein led us to a class of compounds called isothiocyanates. These naturally occurring chemicals found in cruciferous vegetables are known to have certain cancer-fighting properties. However, the potency of these compounds is so low that a successful drug would require large impractical amounts of these compounds. Therefore, isothiocyanates were modified by replacing their sulfur bonds with selenium. Selenium deficiency is common in cancer patients, including those diagnosed with metastatic melanoma. Besides, selenium is also known to destabilize Akt proteins in prostate cancer cells.

To study the effectiveness of isoselenocyanate, mice were injected with cancer cells. Six days later, when the animals developed large tumors, they were divided into two groups and treated separately with either the vegetable compounds or the compounds supplemented with selenium. Tests on mice suggest that these compounds, when combined with selenium, target melanoma tumors more safely and effectively than conventional therapy. Newly developed selenium-enhanced compounds significantly reduced the production of Akt3 protein and shut down its signaling network.

A grant from The Susan Fazio Foundation for Melanoma Research through the Melanoma Research Foundation's grant program has supported the development and characterization of isoselocyanates for the treatment of melanoma. The study, titled "Targeting Akt3 Signaling in malignant melanoma using Isoselenocyanates," appeared in the March 1, 2009, issue of Clinical Cancer Research. The use of naturally occurring compounds that target cancer-causing proteins could lead to more effective ways of treating melanoma.

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Dr. Xiauwei Xu

2006 – Dr. Xiauwei Xu

Erythropoietin is widely used clinically to treat anemia associated with various clinical conditions including cancer. Data from several clinical trials suggest significant adverse effect of erythropoietin treatment on cancer patient survival. However, controversy exists whether erythropoietin receptor is functional in cancer cells. In this study, we demonstrate that erythropoietin receptor expression is detectable in 90.1% of 65 melanoma cell lines, and increased copy number of the erythropoietin and erythropoietin receptor loci occur in 30% and 24.6% of 130 primary melanomas, respectively. Erythropoietin receptor is functional and plays an essential role in melanoma cell survival and tumorigenesis in vivo. Constitutive activation of EpoR promotes melanoma progression. Although daily administration of recombinant erythropoietin fails to stimulate melanoma growth in vivo, erythropoietin treatment results in increased local recurrence after excision of the primary tumors. Inhibition of erythropoietin results in decreased angiogenesis induced by melanoma cells. Our data indicate that EpoR is essential for melanoma survival. The potential effect of exogenous erythropoietin may depend not only on the presence of erythropoietin receptor on tumor cells, but also on the tumor microenvironment. These results suggest that erythropoietin receptor may represent a potential therapeutic target for melanoma.

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