Samlowski Lab
Wolfram Samlowski, M.D.
Head of the Section of Melanoma, Renal Cancer and Immunotherapy
Dr. Samlowski received his B.A. and M.D. from The Ohio State University. He completed a residency in internal medicine at Wayne State University in 1981, as well as a clinical fellowship in hematology/oncology at the University of Utah School of Medicine in 1984. He is board certified in internal medicine and oncology. Formerly,
Dr. Samlowski was a member of the faculty at the University of Utah and the Huntsman Cancer Institute, Salt Lake City, from 1984 to 2007, rising to the rank of professor in the Division of Oncology.
Dr. Samlowski has served as a member of the National Comprehensive Cancer Network Practice Guidelines Committee for melanoma and renal carcinoma for a number of years. In July of 2007, he joined the faculty of Nevada Cancer Institute (NVCI).
Dr. Samlowski specializes in the treatment of melanoma and kidney cancer with emphasis on treatments that activate the immune system to fight these cancers. He is involved in translational research—the development of new ideas and treatments derived from laboratory experiments into actual cancer treatments for patients. Dr. Samlowski believes that current melanoma and renal cancer treatments are unsatisfactory, because they cure only a small percentage of patients with advanced disease. He is very interested in identifying effective new cancer drugs and obtaining these for clinical testing at the NVCI. These clinical trials provide hope for patients when standard treatments have not proven useful.
Laboratory Members
John McGregor, laboratory supervisor
Shweta Tharkar
Erika Samlowski
Sreekanth Donepudi, postdoctoral fellow
Research Interest
The Samlowski lab is involved in translational research and development of novel cancer immunotherapy agents. The lab evaluates promising new drugs using cellular and molecular studies, as well as cancer treatment trials using preclinical models. Our goal is to move promising new drugs into human cancer treatment trials that incorporate correlative biologic studies designed to verify important intermediate endpoints or markers for drug activity.
Specific areas of work include the following:
Development of agents designed to prevent side effects from cytokine treatment (for example, high-dose IL-2). Laboratory studies have identified novel mechanisms that cause cytokine-induced hypotension and vascular leak syndrome. These experimental findings have allowed development of a number of new drugs to prevent side effects. Two of the agents tested have reached Phase I clinical testing.
Besides our work on CD26, we also actively participate in clinical trials developing novel therapeutic agents for the treatment of lymphomas. Our published work has led to a better understanding of the role of selected targeted therapies in lymphomas.
Evaluation of novel delivery systems for cytokines, such as IL-2 using thermosensitive polymers and gene therapy.
Evaluation of SALL4 as a melanoma stem cell marker.
Research Efforts
Work focuses on both clinical and research areas and includes the following:
Preclinical Research
Translational Studies
Clinical Trials
For more information, please contact:
Gina Molina, Administrative Assistant
(7020) 822-5118
gmolina@nvcancer.org
Preclinical Research
Thermosensitive Biopolymer Delivery System for Cytokines (IL-2) In collaboration with Protherics, Dr. Samlowski has performed preclinical testing of a delivery vehicle for sustained release of drugs for direct tumor injection. This involves dissolving IL-2 in a thermosensitive polymer that is liquid at room temperature and polymerizes at body temperature (ReGel). The hypothesis is that sustained release of a T-cell activating cytokine such as IL-2 in the tumor microenvironment will activate tumor-infiltrating lymphocytes that already have recognized the cancer and result in local and perhaps systemic immune responses against the cancer. The long-term goal is to bring ReGel/IL-2 into clinical testing in cancer patients at NVCI.
IL-2tm Gene Therapy of Cancer
Selective expression of cytokines on the surface of tumors is likely to stimulate tumor-infiltrating lymphocytes that are primed and already recognize tumor antigens. This may result in enhanced tumor recognition and killing. This gene therapy approach may avoid toxicity associated with systemic therapy with high doses of the cytokines needed to achieve the same effects. Further preclinical evaluation of the IL-2tm gene therapy as a possible cancer treatment is underway.
NO Induced Apoptosis and Cell Cycle Inhibition
NO is a potent cellular signaling molecule in normal and neoplastic cells. NO exposure of murine and human tumor cell lines with deletions or mutations of p53 induce apoptosis (programmed cell death) and cell cycle arrest, while expression of wild type p53 paradoxically protected cells. Studies into the mechanism of this p53-related effect are underway in the lab.
Mechanisms of IL-2-Induced Hypotension and Vascular Leak
Interleukin-2 (IL-2) is currently used to treat patients with metastatic renal cell carcinoma and malignant melanoma. Clinical use of IL-2 is limited by severe side effects, particularly hypotension, vascular leak, and neuropsychiatric toxicity. Because of such dose-limiting side effects, the full period of IL-2 dosing is frequently curtailed. The lab has developed unique models to study IL-2 induced hypotension, vascular leak, and neuropsychiatric toxicity.
These models are being used to identify inhibitors that may be used to decrease side effects of IL-2 in patients and increase the does of IL-2 that may be tolerated. These observations have already been translated into clinical trials of inhibitors of superoxide formation and NO scavenging agents based on preclinical studies. This area of research represents an internationally recognized area of expertise in the Samlowski Lab.
Translation Studies
Phase I Trial of PHP with High-Dose IL-2
High-dose interleukin-2 (IL-2) produces complete remissions in a small percentage (five to ten percent) of patients with metastatic renal carcinoma or melanoma. Many of the IL-2-induced complete remissions prove long-lasting, with up to 18-year follow-up. However, the clinical use of IL-2 is limited by severe side effects, including hypotension and vascular leak syndrome (VLS) in particular. Patients treated with high-dose IL-2 require hospitalization for close monitoring and administration of fluids, colloids, and pressor medications to treat low blood pressure that may occur. A substantial fraction (1/3 to ½) of planned IL-2 doses is usually omitted due to cardiovascular toxicity, which may compromise effectiveness.
Laboratory and clinical studies have shown that synthesis of nitric oxide (NO) is strongly induced following IL-2 treatment. NO is an important mediator of hypotension and VLS. A promising new agent, a pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), has recently been identified that appears to be safe in humans and has the potential to prevent both IL-2-induced hypotension and VLS due to its ability to break down NO as well as other potentially injurious oxidative radicals.
A Phase I clinical investigation of PHP in conjunction with high-dose IL-2 treatment is underway to evaluate safety of this compound and to establish an effective dose. The safety of PHP is being assessed in patients with metastatic renal carcinoma or malignant melanoma. This study will establish dose-limiting toxicity (if any) of this agent in combination with high-dose IL-2, and define a biologically effective dose for reversal of IL-2-induced hypotension. The effect of PHP on hemodynamic function in IL-2-treated patients, is being measured, including assessment of blood pressure, systemic vascular resistance, cardiac index, pulmonary artery pressure, capillary wedge pressure, and the total dose of pressors required during each course of high-dose IL-2 treatment. Finally, the potential usefulness of intermediate biomarkers for activation of the NO synthesis pathway in patients treated with IL-2 with or without PHP is being evaluaed, to develop assays for planned Phase II testing.
Knowledge gained from evaluating mechanisms of IL-2 toxicity will likely be broadly relevant in understanding the pathophysiology of hypotension and VLS induced by other cytokines such as IL-1, TNF, VEGF and IL-12.
Phase I trial of decitabine with PEG-Interferon
Expression of genes is regulated by a process termed DNA methylation. Recent studies have shown that DNA methylation is important in silencing repair enzymes, and inducing expression of drug sensitivity or resistance phenotypes. For example, cancer cell sensitivity to interferon-rishi is regulated by DNA methylation of key genes. The nucleoside analogue 5-aza-2'-deoxycytidine (decitabine) is a potent drug that inhibits DNA methylation in vitro. Decitabine-induced effects on gene reactivation require incorporation into DNA followed by several cellular division cycles in vitro. In a previous Phase I trial of decitabine, we established that 2mg/m2/day, given as a 168h continuous i.v. infusion resulted in significantly decreased MAGE-1 promoter-specific and total genomic DNA methylation with minimal toxicity.
Further preclinical studies suggested that the interferon-signaling pathway is reactivated following decitabine exposure of cancer cells. Building on this experience, a Phase I clinical trial to test whether a decitabine infusion can sensitize cancer cells to interferon-α in vivo is being performed. This trial will assess the toxicities of repeated small intravenous doses of decitabine with escalating weekly doses of subcutaneous PEG-IFN in patients with refractory and metastatic cancers. The clinical protocol is designed to identify the dose limiting toxicity and the maximum tolerated dose of PEG-IFN in this combination.
Molecular correlation studies are being performed to evaluate pretreatment and post treatment samples of blood, skin and tumor from patients to identify changes in global (genomic) DNA methylation, as well as evaluating promoter-specific methylation. Additional experiments will evaluate interferon signaling and DNA damage response pathways in normal and neoplastic cells.
This study will test whether decitabine can increase clinical activity of interferon in sensitive and resistant cancers with acceptable safety.
Evaluation of the role of SALL4 as a melanoma stem cell marker
Current evidence suggests that most human tumors contain a small percentage of tumor “stem cells.” These cancer progenitor cells are thought to undergo self-replication and differentiation, both maintaining and expanding a population of undifferentiated tumor cells, while generating a much-amplified number of more mature tumor cells. Tumor stem cells are likely to mediate both cancer growth and dormancy. Increasing stem cell frequency in pigmented lesions is likely to correlate with invasiveness, as well as metastatic potential. Failure to eradicate this drug-resistant cell population is likely to be the cause of eventual treatment failure in advanced melanoma.
In recent years, studies by Dr. Yupo Ma at NVCI have identified SALL4 as a potential tumor stem cell marker in human hematopoietic and epithelial neoplasms. Ongoing experiments are designed to identify cell surface markers that associate with melanoma stem cells, as well as better characterize the functional characteristics of these rare cells. Studies to characterize SALL4 expression on biopsies of normal skin, normal and dysplastic nevi, Spitz nevi, primary melanoma, as well as in sentinel lymph node biopsies (either negative for cancer or containing microscopic metastases) are also underway. The relationship of serum levels of SALL4 with tumor stage is being tested. Planned studies will quantify serum levels in patients with metastatic, regionally advanced and localized melanoma, and normal controls.
This line of investigation is designed to identify and characterize melanoma stem cells, with the goal of developing better markers to predict prognosis. This may also allow more accurate characterization of a patient’s cancer stage and response to treatment.
Clinical Trials
Dr. Samlowski is performing a significant number of clinical trials at NVCI. These include investigator initiated, pharmaceutical company sponsored and cooperative group trials.
These innovative trials of new drugs are designed to prevent cancer recurrence in high-risk melanoma and kidney cancer, as well as to provide more effective treatment of metastatic disease.
Another area of focus in this clinical research program is directed at improving the treatment of brain metastases derived from melanoma and kidney cancer.
Twenty-five years ago, when Dr. Samlowski began treating patients, metastatic kidney cancer or metastatic melanoma were invariably fatal. During the last 20 years, he contributed to key studies that resulted in 5% long-term survivorship. The goal for the upcoming years is to push long-term survivorship to even higher levels.
“Development of new anti-cancer agents via clinical trials is driven by heart, hustle and desire.”
Publications
Samlowski WE, Jensen RL, Shrieve DC. Multimodality management of brain metastases in metastatic melanoma patients. Exp Rev Anticancer Ther 7:1699-1705, 2007.
Samlowski WE, Vogelzang NJ. Emerging drugs for treatment of metastatic renal cancer. Expert Opin Emerging Drugs 12:605-618, 2007.
Cotter MA, Thomas J, Cassidy P, Robinette K, Jenkins N, Florell SR, Leachman SA, Samlowski WE, Grossman D. N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of UV-induced melanoma in mice. Clin Cancer Res 13:5952-5958, 2007.
Houghton AN, Coit DG, Daud A, Dilawari RA, Dimaio D, Gollob JA, Haas NB, Halpern A, Johnson TM, Kashani-Sabet M, Kraybill WG, Lange JR, Martini M, Ross MI, Samlowski WE, Sener SF, Tanabe KK, Thompson JA, Trisal V, Urist MM, Walker MJ. Melanoma: Clinical practice guidelines in oncology. J Natl Compr Canc Netw 4:666-84, 2006.
Motzer RJ, Bolger GB, Boston B, Carducci MA, Fishman M, Hancock SL, Hauke RJ, Hudes GR, Jonash E, Kantoff P, Kuzel T, Lange PH, Levine EG, Logothetis C, Margolin KA, Pohar K, Redman BG, Robertson CN, Samlowski WE, Sheinfeld J. Kidney Cancer: Clinical practice guidelines in oncology. J Natl Compr Canc Netw 4:1072-1081, 2006.
