Team Science At Its Best: Pioneering Research Is Made Possible By A National Grant
Tapping into Moffitt Cancer Center’s culture of teamwork and adaptability, Moffitt physician-scientists are exploring innovative approaches to skin cancer treatment with the aim of bringing – quickly – new science discoveries from the laboratory to patient clinical trials. This is important because melanoma is the most lethal skin cancer, and it is the second most common form of cancer for young people between the ages of 15 to 29.
Some pioneering melanoma clinical trials at Moffitt are made possible by a newly awarded National Cancer Institute (NCI) Specialized Programs of Research Excellence (SPORE) grant for melanoma research. The SPORE grant, which is being overseen by principal investigator Jeffrey S. Weber, M.D., Ph.D.
, director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence, totals $8,829,020 over five years. This is Moffitt’s second SPORE grant. The first, for lung cancer research, was awarded in 2008. Moffitt is the only cancer center based in Florida that has received this prestigious grant.
“SPORE grants were established to promote interdisciplinary research and help move basic findings from the laboratory to a clinical setting,” says Dr. Weber. “The addition of a melanoma SPORE acknowledges the translational research being done by our Comprehensive Melanoma Research Center of Excellence
. We are honored to be recognized by the NCI, and this grant will allow us to significantly enhance our efforts to contribute to the prevention and cure of skin cancer.”
The melanoma SPORE grant has been several years in the making. In 2007, Moffitt was awarded a melanoma SPORE planning grant from Florida’s Bankhead-Coley Cancer Research Program spearheaded by Vernon K. Sondak, M.D.
, chair of Moffitt’s Department of Cutaneous Oncology, to help recruit a team of interdisciplinary skin cancer researchers. That same year, Donald A. Adam, a melanoma survivor and banker, donated $20.4 million to Moffitt for expanding expertise in the area of melanoma research. The gift led to the development of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence and facilitated the recruitment of Dr. Weber.
The new SPORE grant will fund three melanoma research projects that have a common thematic approach designed to promote progress in skin cancer treatment based on novel and promising research. All three projects deal with stage IV disease, with the goal of keeping patients alive longer with a better quality of life.
Project 1: Potentiating the effects of targeted and cytotoxic agents on cell-based immunotherapy in melanoma
: Jeffrey S. Weber, M.D., Ph.D., and Dmitry I. Gabrilovich, M.D., Ph.D., of The Wistar Institute in Philadelphia
This unique project studies targeted therapy with adoptive transfer of T cells with the goal of boosting the immune system’s response against melanoma cells. “This project includes a clinical trial that explores a novel notion that targeted therapy and chemotherapies depend on the immune system for their activity,” says Dr. Weber. “Moffitt is conducting one of only two such trials in the U.S.”
The clinical trial tests the combined effect of adoptive T-cell transfer and drug therapy to inhibit the BRAF mutation in patients with melanoma. It is based on an observation by Moffitt researchers that targeted therapy may prime the immune system and add to the effects of adoptive therapy with therapeutic tumor-infiltrating lymphocytes (TIL) – a preparation of immune cells cultured in the laboratory that when infused into a patient can help break down tumors. Moffitt is one of three centers in the country combining adoptive cell therapy with TIL for melanoma.
Project 2: Abrogation of therapeutic escape pathways in BRAF-mutant melanoma
: Vernon K. Sondak, M.D., and Keiran S. Smalley, Ph.D.
This project seeks to determine why some patients develop resistance to BRAF inhibitors like vemurafenib, a drug approved by the Food and Drug Administration for treatment of BRAF mutation-positive metastatic melanoma. The investigators aim to find whether the resistance can be overcome or if different treatment options are necessary.
Resistance to vemurafenib can develop as early as six months after treatment begins. This clinical trial combines previously used agents that show promise of improving results for BRAF V600-mutated melanoma patients. The study goal is to overcome pathway resistance in melanoma by determining the best and safest dose of an experimental drug, XL888, when administered orally with vemurafenib.
Phase I of this study opened in August 2012 and continued through the end of 2013. Currently, six patients are enrolled and receiving treatment. Four of those participants have had an antitumor response.
Another facet of this project is to determine whether resistance to BRAF inhibition can be overcome using heat shock protein inhibitors. The researchers will perform correlative studies in tumor specimens to determine if XL888 can inhibit a heat shock protein known as Hsp90 and assess how changes in the expression of this key signaling protein relates to a patient’s response.
“The clinical trial will potentially support the use of heat shock inhibitors to overcome resistance to BRAF inhibition in phase II and III trials, redefining how we look at resistance to targeted therapies,” Dr. Weber says.
Project 3: Augmenting the immunogenicity of melanoma through manipulation of histone deacetylases (HDACs)
: Eduardo Sotomayor, M.D.
; Ed Seto, Ph.D.
; and Jeffrey S. Weber, M.D., Ph.D.
This innovative research looks at specific histone deacetylases (HDACs), enzymes that regulate gene expression, to determine if they can be manipulated by an inhibitor drug to stimulate the immune system’s response against melanoma cells.
HDAC inhibitors represent a promising new class of compounds for the treatment of cancer. In this project, HDAC inhibitor LBH-589 will be used in combination with other drugs to treat solid melanoma tumors. The hope is that the LBH-589 will augment the immune system’s response against melanoma cells through suppression of HDAC 6 and 11, enzymes needed for cancer cells to grow and survive.
“The project is new, because to date nobody has used an HDAC inhibitor in a clinical trial to show that it can function as an immune stimulant,” Dr. Weber says. “Additionally, it is a new concept that LBH-589 has immunological effects. Drugs whose effectiveness was thought to lie elsewhere are turning out to work with the immune system.”
It is hoped that knowledge in this area to be generated by the team effort will lead to novel epigenetic-based immunotherapy that will overcome the substantial barrier of melanoma-induced T-cell tolerance.
New Clinical Trials: Not Just For The Hopeless
“Previously, people thought of clinical trials as only for patients who had no hope. That’s not true in this day and age,” says Ragini Kudchadkar, M.D.
, a co-director of the Administration and Clinical Trials Core of the SPORE grant. “Today, clinical trials are all about finding better therapies and drugs. They give patients the opportunity to gain access to drugs they normally couldn’t obtain, and many of the participating patients say they feel good about helping develop therapies for the future.” Dr. Kudchadkar is the principal investigator on a number of clinical trials for patients with advanced-stage BRAF-mutated melanoma, including a phase I study of XL888 with vemurafenib, a phase Ib/II study of LGX818 combined with MEK162 and a phase I/II study of PI3K inhibition with PX-866 combined with vemurafenib.
“People are positive and feel rewarded about enrolling in a clinical trial, even if the outcome is unknown, because they realize that they might help someone in the future. Today, the standard of care for most melanoma patients is to participate in a clinical trial,” Dr. Weber says.