Melanoma: Gollob JA

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, Anonymous00370. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #16884669 No free full text.

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Gollob JA, Wilhelm S, Carter C, Kelley SL. · Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA. · Semin Oncol. · Pubmed #16890795 No free full text.

Abstract: Improvements in our understanding of the molecular basis of cancer have led to the clinical development of protein kinase inhibitors, which target pivotal molecules involved in intracellular signaling pathways implicated in tumorigenesis and progression. These novel targeted agents have demonstrated activity against a wide range of solid tumors, are generally better tolerated than standard chemotherapeutics, and may revolutionize the management of advanced refractory cancer. The ubiquitous Raf serine/threonine kinases are pivotal molecules within the Raf/mitogen extracellular kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway, which regulates cellular proliferation and survival. Raf kinase isoforms (wild-type Raf-1 or the b-raf V600E oncogene) are overactivated in a variety of solid tumor types, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), melanoma, and papillary thyroid carcinoma. In this review, the role of Raf in normal cells and in cancer is discussed, and an overview is given of Raf inhibitors currently in development, focusing on sorafenib tosylate (BAY 43-9006 or sorafenib). Sorafenib is the first oral multi-kinase inhibitor to be developed that targets Raf kinases (Raf-1, wild-type B-Raf, and b-raf V600E), in addition to receptor tyrosine kinases associated with angiogenesis (vascular endothelial growth factor receptor [VEGFR]-2/-3, platelet-derived growth factor receptor [PDGFR]-beta) or tumor progression (Flt-3, c-kit). Preclinical and clinical sorafenib data that led to its recent approval for the treatment of advanced RCC are summarized, along with current thinking on sorafenib's mechanism of effect on the tumor and tumor vasculature in melanoma and RCC.

Gollob JA, Bonomi P. · Duke University Medical Center Durham, NC 27710, USA. · Oncology (Williston Park). · Pubmed #16773840 No free full text.

Abstract: Although improved survival is the "gold standard" for proving clinical benefit of oncologic therapy, the U.S. Food and Drug Administration (FDA) has accepted significant results in clinical trials using surrogate endpoints as the basis for drug approval. One surrogate is the amount of tumor reduction, or tumor response. Although tumor shrinkage would seem to be a necessary precondition for improved survival, clinical studies of a variety of oncologic agents have not consistently demonstrated a correlation between the two in patients with renal cell carcinoma. Moreover, tumor response may not be an appropriate endpoint for evaluating the effects of the new targeted therapies, whose putative mechanisms are generally cytostatic rather than cytotoxic. Clinical trials suggest that some patients with other solid tumors, such as lung cancer, may derive clinical benefit from treatment that helps stabilize their disease. There is also controversy as to whether the Response Evaluation Criteria in Solid Tumors (RECIST) provides the most appropriate instrument for assessing tumor burden. Ultimately, use of a variety of endpoints as well as different trial designs may provide an adequate basis for investigating the benefits/risks of newer therapies.

Bael TE, Peterson BL, Gollob JA. · Department of Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA. · Melanoma Res. · Pubmed #18337652 No free full text.

Abstract: We conducted a single institution phase II trial to evaluate the tolerability and effectiveness of therapy with arsenic trioxide (ATO) and ascorbic acid (AA) with temozolomide (TMZ) in patients with advanced melanoma. Planned enrollment was for 40 patients. Eligible patients were required to have metastatic melanoma with or without brain metastases, an ECOG performance status of 0-2, and adequate organ function. The primary endpoints were overall response rate and degree of grade 4 toxicity. ATO was administered as a loading dose at 0.25 mg/kg/day for 5 days during week 0, and then twice weekly at 0.35 mg/kg during an 8-week cycle. Each infusion of ATO was followed by an infusion of 1000 mg of AA. TMZ was given at the standard dose of 200 mg/m for 5 days during weeks 1 and 5 of each cycle. Eleven patients were enrolled with 10 evaluable for response, five with central nervous system disease. No responses were seen among the first 10 patients and on the basis of a predetermined stopping rule, the trial was terminated. Common grade 1 and 2 side effects included nausea and vomiting (10), fatigue (six), edema (six), rash (six), and elevated AST or ALT (six). Grade 3 and 4 side effects included nausea and vomiting (three), elevated AST or ALT (two), seizure (one), and renal failure (one). This is the first trial combining ATO with chemotherapy in a solid tumor. ATO and AA were administered in the outpatient setting with TMZ in 11 patients with an acceptable side effect profile. No responses were seen in the first 10 evaluable patients leading to early closure of the study. Further studies using ATO and AA with TMZ with this dosing schedule in advanced melanoma are not warranted.

Gollob JA, Sciambi CJ, Peterson BL, Richmond T, Thoreson M, Moran K, Dressman HK, Jelinek J, Issa JP. · Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA. · Clin Cancer Res. · Pubmed #16899610 links to  free full text

Abstract: PURPOSE: The silencing of gene expression through DNA methylation contributes to defects in antigen presentation and apoptosis in melanoma and renal cell cancer. To determine how a hypomethylating agent would modulate the toxicity and antitumor activity of immunotherapy, we initiated a phase I trial of 5-aza-2'-deoxycytidine (decitabine) plus high-dose interleukin 2 (IL-2). EXPERIMENTAL DESIGN: Patients received s.c. decitabine daily x 5 days on weeks 1 and 2 of a 12-week cycle. High-dose IL-2, consisting of two cycles of IL-2 600,000 IU/kg i.v. q8 hours x 14 doses separated by a 2-week break, was administered starting on week 3. Decitabine was escalated from 0.1 to 0.25 mg/kg. The hypomethylating activity of decitabine was assessed during cycle 1 by measuring hemoglobin F levels and changes in DNA methylation in peripheral blood mononuclear cells. RESULTS: Twenty-one patients with melanoma or renal cell cancer were enrolled. Decitabine did not alter the tolerability of IL-2 but caused grade 4 neutropenia in most patients. Grade 4 neutropenia lasting more than 7 days was the only dose-limiting toxicity, with a trend toward a higher incidence with increasing decitabine doses. Infection occurred in only one patient despite the high incidence of neutropenia, and granulocyte colony-stimulating factor use in several patients expedited neutrophil recovery. Decitabine augmented hemoglobin F levels and altered DNA methylation and gene expression in peripheral blood mononuclear cells in a dose-independent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients. CONCLUSIONS: Decitabine can be safely administered with high-dose IL-2 and may enhance the activity of IL-2 in melanoma.

Gollob JA, Veenstra KG, Parker RA, Mier JW, McDermott DF, Clancy D, Tutin L, Koon H, Atkins MB. · Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · J Clin Oncol. · Pubmed #12829677 No free full text.

Abstract: PURPOSE: To maintain interferon gamma (IFNgamma) induction by recombinant human interleukin-12 (rhIL-12) and enhance its activity against melanoma and renal cell cancer, a regimen of twice-weekly intravenous (IV) rhIL-12 was modified to include concurrent low-dose subcutaneous (SC) IL-2 in a phase I dose escalation study. PATIENTS AND METHODS: Patients received 6-week cycles of twice-weekly IV rhIL-12 at doses of 300 to 500 ng/kg. Midway through cycle 1, low-dose SC IL-2 was added. The IL-2 was escalated from 0.5 to 6.0 MU/m2. Grade 3 elevations of hepatic ALT, AST, or alkaline phosphatase were not considered dose-limiting unless values were more than 10 times normal. During cycle 1, patients underwent immune monitoring to assess the effect of IL-2 on lymphocyte activation and cytokine production induced by rhIL-12. RESULTS: Twenty-eight patients were enrolled onto the study. The maximum-tolerated dose (MTD) was 500 ng/kg rhIL-12 plus 3 MU/m2 IL-2. Toxicities related to the addition of IL-2 at the MTD included fever or chills, anemia, fatigue, nausea or vomiting, and orthostatic hypotension. At the MTD, IL-2 significantly augmented IFNgamma and IFNgamma-inducible protein-10 production by rhIL-12 and led to a three-fold expansion of natural killer cells. There was one major clinical response (partial response) as well as two pathologic responses; all occurred in melanoma patients. Stable disease for three to six cycles was only observed at or above the MTD in melanoma and renal cell cancer patients. CONCLUSION: The addition of concurrent low-dose IL-2 to rhIL-12 is well tolerated, restores and maintains immune activation by rhIL-12, and has clinical activity. This regimen should be further investigated in phase II studies in untreated patients with melanoma or renal cell cancer and in other rhIL-12-responsive malignancies.

Atkins MB, Gollob JA, Sosman JA, McDermott DF, Tutin L, Sorokin P, Parker RA, Mier JW. · Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. · Clin Cancer Res. · Pubmed #12374674 links to  free full text

Abstract: PURPOSE: In an effort to reduce the frequency of central nervous system (CNS) progression in patients with metastatic melanoma with ongoing systemic response to biochemotherapy, we modified our standard concurrent biochemotherapy regimen by replacing dacarbazine (DTIC) with oral temozolomide. Experimental Design: Patients received cisplatin, vinblastine, and temozolomide (20 mg/m(2) cisplatin and 1.2 mg/m(2) vinblastine i.v., days 1-4; 150 mg/m(2) p.o. temozolomide, days 1-4) concurrent with interleukin 2 (9 MIU/m(2)/day) by continuous i.v. infusion on days 1-4 and IFN-alpha (5 MU/m(2)/day) on days 1-5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte-colony stimulating factor and aggressive antiemetics were also provided. Tumor staging included torso computed tomography scans and brain magnetic resonance imaging pretreatment, after cycle 4 and then every 3 months for 2 years. Torso computed tomography scans were also performed after cycle 2. RESULTS: A total of 147 treatment cycles were administered to 48 patients. No patients had received prior chemotherapy or interleukin 2; however, 19 (40%) had received prior adjuvant IFN-alpha. Significant toxicities included 2 deaths from cardiac events (pericarditis al tamponade and posttreatment myocardial infarction with associated ventricular arrhythmia) and 3 gastrointestinal serious adverse events (pancreatitis, appendicitis, and upper GI bleed). No other nonhematological grade 4 toxicities were observed. Tumor responses were seen in 22 of 47 evaluable patients (relative risk, 47%) with 7 complete responses (15%). Response durations ranged from 1 to 29+ months with 1 currently ongoing. Median survival was 7.5 months. The CNS was the initial site of progression in 2 responding patients. An additional 6 responding patients developed CNS progression within 3 months of systemic progression. Initial CNS progression was significantly less frequent what was seen with the prior DTIC-based biochemotherapy regimen (2 of 22 versus 12 of 19; P = 0.001). CONCLUSION: This regimen appears to be active and reasonably well tolerated in patients with metastatic melanoma. Although the substitution of temozolomide for DTIC reduced the incidence of initial CNS progression, this effect did not appear to result in an improved overall outcome.

Fraenkel PG, Rutkove SB, Matheson JK, Fowkes M, Cannon ME, Patti ME, Atkins MB, Gollob JA. · Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. · J Immunother. · Pubmed #12142560 No free full text.

Abstract: Interleukin-2 is an effective agent against renal cell carcinoma and melanoma, but it has been associated with autoimmune sequelae such as hypothyroidism and vitiligo. A 64-year-old man with non-insulin-dependent diabetes and metastatic renal cell carcinoma developed insulin-dependent diabetes after his first cycle of therapy with high-dose (HD) interleukin-2. After additional therapy with interleukin-2, the patient developed generalized myasthenia gravis (MG) and polymyositis, both of which responded to treatment with corticosteroids and plasmapheresis. To investigate the role of IL-2 in the development of these autoimmune complications, autoantibody titers were assayed from serum obtained before and after IL-2 treatment and after treatment with corticosteroids plus plasmapheresis. Before IL-2 treatment, the patient had antibodies directed against insulin, islet cell antigens, and striated muscle. Acetylcholine receptor antibody levels were normal before starting IL-2. After treatment with IL-2, the patient developed acetylcholine receptor binding antibodies and exhibited an increase in the striated muscle antibody titer from 1:40 to 1:160. Recovery from the MG and polymyositis was associated with substantial decreases in the acetylcholine receptor and striated muscle antibody titers. These findings suggest that HD IL-2 accelerated the progression of latent autoimmune diabetes and myositis in this patient whose tolerance to islet cell antigens and striated muscle had already been broken and precipitated a break in tolerance to the acetylcholine receptor resulting in the development of MG. This case demonstrates the importance of prompt recognition of IL-2-induced MG and shows how this complication can be successfully managed with aggressive therapy.

Gollob JA, Mier JW, Veenstra K, McDermott DF, Clancy D, Clancy M, Atkins MB. · Beth Israel Deaconess Medical Center, Division of Hematology/Oncology, Boston, Massachusetts 02215, USA. · Clin Cancer Res. · Pubmed #10815886 links to  free full text

Abstract: The aim of this study was to examine the tolerability, antitumor activity, and biological effects of a new schedule of i.v. recombinant human interleukin 12 (rhIL-12). Twenty-eight patients were enrolled in a Phase I trial in which rhIL-12 was administered twice weekly as an i.v. bolus for 6 weeks. Stable or responding patients were eligible to receive additional 6-week cycles until there was no evidence of disease or until tumor progression. Patient cohorts were treated with escalating doses of rhIL-12 (30-700 ng/kg). The maximum tolerated dose (MTD) was 500 ng/kg, with dose-limiting toxicities consisting of elevated hepatic transaminases and cytopenias. At the MTD (n = 14), there was one partial response occurring after 6 cycles of rhIL-12 in a patient with renal cell cancer. Two additional renal cell cancer patients treated at the MTD had prolonged disease stabilization, with one of these exhibiting tumor regression after 8 cycles of rhIL-12. IFN-gamma, IL-15, and IL-18 were induced in patients treated with rhIL-12. Whereas IFN-gamma and IL-15 induction were attenuated midway through the first cycle in patients with disease progression, those patients with tumor regression or prolonged disease stabilization were able to maintain IFN-gamma, IL-15, and IL-18 induction. The down-modulation of IFN-gamma induction during rhIL-12 treatment did not relate to IL-10 production or alterations in rhIL-12 bioavailability but was associated with an acquired defect in lymphocyte IFN-gamma production in response to IL-12, IL-2, or IL-15. This defect could be partially overcome in vitro through combined stimulation with IL-12 plus IL-2. These findings show that the chronic administration of twice-weekly i.v. rhIL-12 is well-tolerated, stimulates the production of IL-12 costimulatory cytokines and IFN-gamma, and can induce delayed tumor regression. Strategies aimed at maintaining IFN-gamma induction, such as the addition of IL-2, may further augment the response rate to this schedule of rhIL-12.

Gollob JA, Sciambi CJ. · Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC 27710, USA. · Clin Cancer Res. · Pubmed #17785578 links to  free full text

Abstract: PURPOSE: Metastatic uveal melanoma is resistant to conventional chemotherapy and immunotherapy. In this study, we investigated the responsiveness of uveal melanoma cell lines to IFNs and the hypomethylating agent decitabine. EXPERIMENTAL DESIGN: The uveal melanoma cell lines 92-1, UW-1, OCM-1, and MKT-BR were exposed to varying concentrations of IFN-alpha, IFN-gamma, and decitabine, alone and in combination. The effects of decitabine on gene expression were examined using DNA microarray analysis. RESULTS: We found that IFN-gamma and decitabine induced cell death in uveal melanoma. Whereas a high concentration of IFN-gamma (1,000 units/mL) was required to induce cell death, we observed a dose-related increase in cell death when decitabine was used at a range of 0.1 to 10 micromol/L. Strikingly, 1 micromol/L decitabine synergized with 10 to 1,000 units/mL IFN-gamma to induce massive cell death. In contrast, decitabine had no effect on three cutaneous melanoma cell lines and exhibited no synergy with either IFN. In uveal melanoma, decitabine up-regulated the expression of genes involved in growth control and apoptosis and down-regulated genes that have been implicated in the malignant phenotype of cutaneous melanoma. The gene up-regulated to the greatest degree by decitabine and whose expression showed a dose-effect across the three concentrations of decitabine was S100A2, a putative tumor suppressor. The genes modulated by decitabine in uveal melanoma were largely unaffected in cutaneous melanoma. CONCLUSIONS: These findings form a basis for testing the decitabine/IFN-gamma combination in metastatic uveal melanoma and for exploring the role of S100A2 in the susceptibility of uveal melanoma to IFN-mediated cell death.

Gollob JA, Sciambi CJ, Huang Z, Dressman HK. · Division of Medical Oncology and Transplantation, Department of Medicine, Duke University, Durham, NC, USA. · Cancer Res. · Pubmed #16204058 links to  free full text

Abstract: IFN-gamma plays a role in the response to melanoma indirectly through its effect on the immune system and directly through its antiproliferative and proapoptotic effects on melanoma cells. To understand the molecular basis for the direct antimelanoma effect of IFN-gamma, we studied IFN-induced changes in gene expression and signaling among three human melanoma cell lines (DM6, DM93, and 501mel). These were resistant to the antimelanoma effect of IFN-alpha, and only DM6 cells exhibited growth inhibition and apoptosis with IFN-gamma. Through DNA microarray analysis, we found that the antimelanoma effect of IFN-gamma in DM6 was associated with the down-regulation of multiple genes involved in G-protein signaling and phospholipase C activation (including Rap2B and calpain 3) as well as the down-regulation of genes involved in melanocyte/melanoma survival (MITF and SLUG), apoptosis inhibition (Bcl2A1 and galectin-3), and cell cycling (CDK2). The antimelanoma effect of IFN-gamma was also associated with the up-regulation of the proapoptotic dependence receptor UNC5H2 and the Wnt inhibitor Dkk-1. Whereas both IFNs were able to activate Stat1 in all cell lines, the delayed activation of the extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases occurred only in DM6 with IFN-gamma, and the effect of IFN-gamma on cell growth and survival as well as gene expression in DM6 was dependent on the coordinate activation of MEK1 and p38. These findings provide new insights into the signaling events and gene expression changes associated with growth inhibition and apoptosis in melanoma and may thereby assist in identifying new targets for the treatment of melanoma.