The Diversity of BCR-ABL Fusion Proteins and Their Relationship to Leukemia Phenotype

Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non–small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8–9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free ( P = 0.034) and overall survival ( P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.

Significance: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit. Cancer Discovery; 1(7) ; 598–607. ©2011 AACR .

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https://cancerdiscovery.aacrjournals.org/content/candisc/1/7/598.full.pdf

Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer

Methylation of DNA is a biochemical modification that can influence gene expression and is involved in inactivating one of the two X chromosomes in women. Evidence that has accumulated in the past 10 years suggests that cancer cells usurp this physiologic mechanism and use it to their benefit by inactivating tumor suppressor genes and related proteins. However, the primary structure of the affected proteins remains intact; reversal of abnormalities in DNA methylation may therefore restore the tumor-suppressive function of these genes and provide a novel approach to cancer therapy. Two demethylating drugs, 5-azacytidine and 5-aza-deoxycytidine, are currently being tested in clinical trials, and several others are in preclinical development. In this article, the biological rationale for targeting aberrant methylation in cancer therapy is reviewed and completed phase I and II trials of this approach, some of which show promise for treatment of hematologic malignancies, are summarized.

Changes in DNA Methylation in Neoplasia: Pathophysiology and Therapeutic Implications

DNA methyltransferase inhibitors—state of the art

Clinical studies involving 5-azacytidine, a ring analogue of cytidine, began in Europe in 1967 and the United States in 1970, and we review available preclinical and clinical studies here. The drug possesses cytotoxic, antimicrobial, antineoplastic, abortive, and mutagenic activity in various biological systems. 5-Azacytidine is thought to exert its antineoplastic effect through interference with nucleic acid metabolism. The dose-limiting toxicities are nausea, vomiting, and leukopenia, while the incidence of thrombocytopenia is low. Hepatic toxicity ranges from abnormal findings in liver function tests to hepatic coma. Clinical results in solid tumors are not encouraging, but 5-azacytidine shows consistent antitumor activity in patients with acute myelogenous leukemia resistant to previous treatment. An overall response rate of 36%, with 20% complete remissions, was achieved in 200 previously treated patients with acute myelogenous leukemia. Further studies must define the role of 5-azacytidine alone and in combination for the first-line treatment of acute myelogenous leukemia.

5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia.

A Phase I clinical trial of emetine hydrochloride (NSC‐33669) in adults with solid tumors was conducted using two time schedules: a. a single subcutaneous dose daily for 10 days, and b. a single subcutaneous injection every 4 days (q4d) for 10 doses. Thirty‐two patients were treated on the daily schedule with doses ranging from 1.0–2.0 mg/kg/day, and nine patients were treated in the q4d schedule with doses ranging from 1.2–2.2 mg/kg/dose. Toxicity was similar in both groups and consisted of pain at the injection site, muscle weakness and myalgia, elevations in creatine phosphokinase, and electrocardiographic abnormalities. Muscle weakness was the dose‐limiting toxicity. The maximum tolerable total dose was 10 mg/kg. No response was noted in 16 patients evaluated.

A phase I study of emetine hydrochloride (NSC 33669) in solid tumors.

Thirty patients with various solid tumors were treated with 5-azacytidine. Total doses ranged from 1.0 to 24.0 mg/kg and were given over a minimal period of 8 days. The major toxic effect was hematologic with significant leukopenia and thrombocytopenia usually occurring 20-30 days after the start of therapy, especially at higher dose levels. The marrow depression lasted 1-5 weeks and was fully reversible. Nausea and mild diarrhea were common following injection of the drug. Serum glutamic oxaloacetic transaminase levels rose in several patients. No other evidence of hepatic toxicity was seen. Objective remissions were noted in seven of 11 patients with cancer of the breast, two of five with melanoma, and two of six with cancer of the colon.

Phase I study of 5-azacytidine (NSC-102816) .

Tubercidin with EDTA has been given a Phase I clinical trial in 45 patients. The drug was mixed with approximately 500 ml blood withdrawn from the patient, with EDTA as an anticoagulant, and after 1 hr incubation at 37°, given intravenously to the patient. The dose levels ranged from 200 to 1500 μg/kg given at weekly intervals for two doses. Toxicity to the drug was uncommon and usually not severe. Hematological toxicity was noted in six patients, renal toxicity in five patients, hepatic toxicity in two patients, and severe gastrointestinal toxicity in one patient. Objective regression of the tumor was noted in four patients. The biological effect was apparent between 4 and 12 weeks after onset of therapy and was transitory.

https://cancerres.aacrjournals.org/content/canres/30/1/79.full.pdf

Arthur J. Weiss

Papers

A phase I study of emetine hydrochloride (NSC 33669) in solid tumors.

Phase I study of 5-azacytidine (NSC-102816) .

Clinical studies with tubercidin administered after absorption into human erythrocytes.

Clinical trial with subcutaneously administered 5-azacytidine (NSC-102816).

Historical communication: Philadelphia-positive chronic myelogenous leukemia followed for 27 years.