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Modulation of Classical Multidrug Resistance and Drug Resistance in General
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Most anticancer drugs and ionizing radiation exert their therapeutic effects by activating apoptosis or programmed cell death. The expression of proteins involved in apoptosis is a major determinant of sensitivity to therapies (10,11,13–15,93–95). In addition to Bcl-2, which is oncogenic in many B-cell lymphomas, by chromosomal translocations, Bcl-xl and Mcl-1 are also anti-apoptotic proteins that can confer resistance to therapies (11,95). Inhibitors of these proteins are being investigated in hematologic cancers. Oblimersen, an antisense phosphorothioate drug targeting the Bcl-2 gene, has shown some activity when combined with fludarabine in chronic lymphocytic leukemias, with remission rates of 7% versus 17% (96). Small molecule inhibitors of the BH3 domain shared by the Bcl-2, Bcl-xl, and Mcl-1 proteins are being studied in lymphomas and multiple myeloma (97–100).
Overview of Molecular Pathways in Melanoma
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
Bcl-2, an inhibitor of apoptosis protein, can modulate cytochrome c release and APAF-1/procaspase-9 interaction and is overexpressed in melanoma (110). Oblimersen sodium (Genasense, Genta Inc., Berkeley Heights, New Jersey, U.S.) is an antisense oligonucleotide designed to block such inhibition, enhancing cytotoxic antitumor effects. Unfortunately, only small improvements in response rate, complete response, and PFS were seen when DTIC in combination with oblimersen was compared with single agent DTIC in a randomized phase III study in advanced unresectable melanoma (111). On subset analysis, there was a survival benefit in patients with normal serum lactate dehydrogenase (LDH). Thus, a phase 3 randomized double-blind, placebo controlled trial of oblimersen plus dacarbazine versus dacarbazine alone in advanced melanoma (AGENDA) was designed for patients with normal LDH.
Other Novel Targeted Therapies in Lung Cancer
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Kyriakos P. Papadopoulos, Anthony W. Tolcher
Downregulation of Bcl-2 and Bcl-xL by antisense is sufficient in some models to induce apoptotic cell death. Not surprisingly, in light of the extensive body of work highlighting its critical role in abrogating cell death, Bcl-2 has been the early focus of ASO targeting (41). The anti Bcl-2 mRNA agent furthest advanced in clinical testing is oblimersen (G3139, Genasense™, Genta, Berkely Heights, New Jersey, U.S.A.). Oblimersen is an 18-base antisense phosphorothioate oligonucleotide targeting the first six codons of the human Bcl-2 mRNA open reading frame. Preclinical in vitro and lung cancer xenograft models have demonstrated the activity of oblimersen in decreasing Bcl-2 mRNA and protein levels, inhibiting tumor growth and increasing survival (42). In tumors where diminished apoptosis may not be critical to cell survival but is only one component of chemoresistance, oblimersen may function to enhance sensitivity of tumors to chemotherapy. Following from this, several combination studies have been conducted with oblimersen and a variety of chemotherapeutic agents including docetaxel (43,44). In lung cancer in particular, oblimersen was combined with carboplatin and etoposide in a phase-I trial of 16 patients with untreated extensive stage SCLC (45). The regimen appeared to be well tolerated and of 14 evaluable patients, 86% had a partial response (PR). Notably no evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed. A second phase-I trial of oblimersen and paclitaxel in chemorefractory SCLC patients found the regimen to be tolerable but no responses were observed in 12 patients treated (46). A randomized phase-II study of docetaxel with or without oblimersen has been undertaken in previously treated NSCLC patients but no results from this trial are available. Three phase-III randomized trials, respectively, in myeloma, melanoma, and chronic lymphocytic leukemia (CLL) addressing whether oblimersen improves the efficacy of standard chemotherapy have yielded positive results only for CLL and its role, if any, in the treatment of lung cancer remains to be defined (47–49). Next generation ASO with locked nucleic acid modifications that have higher target affinity and stability are under clinical development (50,51). Second-generation antisense Bcl-xL oligonucleotide has been shown to effectively induce apoptosis in lung adenocarcinoma cell lines (52), and bispecific oligonucleotides targeting the mRNA homology region of both Bcl-2 and Bcl-xL have shown preclinical efficacy in inducing apoptosis in vitro in NSCLC and SCLC cells (53).
Efficacy of nab-paclitaxel in treating metastatic melanoma
Published in Expert Opinion on Pharmacotherapy, 2019
The combination of oblimersen, temozolomide, and nab-paclitaxel was well tolerated and demonstrated encouraging activity in patients with advanced melanoma [24]. Oblimersen is an 18-base phosphorothioate antisense oligonucleotide, which binds bcl-2 mRNA leading to RNA cleavage by RNase H. In a phase I trial, 32 chemotherapy-naïve patients with metastatic melanoma and normal LDH levels were enrolled on 3 cohorts. The treatment regimen consisted of 56-day cycles of oblimersen (7 mg/kg/day continuous IV infusion on day 1–7 and 22–28 in cohort 1 and 2; 900 mg fixed dose, twice weekly in weeks 1–2, 4–5 for cohort 3), temozolomide (75 mg/m(2), days 1–42), and nab-paclitaxel (175 mg/m2 in cohort 1 and 3, 260 mg/m2 in cohort 2 on day 7 and 28). Six grade 3 events (neutropenia, renal insufficiency, hyponatremia, elevated creatinine, allergic reaction, and neuropathy) and 2 grade 4 events (neutropenia and thrombocytopenia) were reported. The objective response rate and disease control rate (DCR) was 40.6% (complete response [CR]: 6.3% and 75%, respectively. Median PFS was 5.3 months and PFS6 was 34.4%. Median OS was 11.1 months and 1-year OS (OS12) was 50% [24].
A concise review of BCL-2 inhibition in acute myeloid leukemia
Published in Expert Review of Hematology, 2018
Meera Yogarajah, Richard M. Stone
Oblimersen is a BCL-2 antisense oligonucleotide that increases tumor cell apoptosis and overcomes chemoresistance by binding to BCL-2 mRNA, thus down regulating BCL-2 expression [44,45]. A phase I study evaluated oblimersen in relapsed/refractory AML in combination with FLAG (Fludarabine, cytarabine, GCSF) salvage chemotherapy [46]. Seventeen patients with relapsed and refractory AML were recruited; eight (29%) achieved CR and two patients achieved CR with incomplete count recovery (CRi) (11%) yielding an objective response of 41%. Another phase I study was conducted in elderly patients in which the agent was combined with standard induction therapy followed by consolidation with cytarabine [47]. The combination achieved 48% CR which was not significantly different than previously reported remission rates of 40% in the absence of oblimersen. However, 50% of the patients who achieved CR remained in remission at a follow-up of 12.6 months which represented a more durable response than would have been expected with standard chemotherapy alone. Moreover, the combination was well tolerated with no increase in adverse events. BCl-2 mRNA and protein levels in BM samples decreased in response to oblimersen compared to baseline in responders but in nonresponders evidenced little change.
Potential of BCL2 as a target for chronic lymphocytic leukemia treatment
Published in Expert Review of Hematology, 2018
Riccardo Moia, Fary Diop, Chiara Favini, Ahad Ahmed Kodipad, Gianluca Gaidano
Induction of apoptosis to inhibit tumor survival has always been a major goal in cancer research. Interfering with the interaction between BCL2 and BH3-only proteins has been initially attempted with approaches based on antisense oligonucleotides, such as oblimersen, that bind to BCL2 mRNA. Oblimersen is able to downregulate the expression of BCL2 in vitro [35], but in the initial phase 1–2 clinical trial displayed a modest single-agent activity [36]. The subsequent phase 3 study (a randomized trial of fludarabine/cyclophosphamide with or without oblimersen) showed that oblimersen, in addition to fludarabine/cyclophosphamide, failed to improve CLL survival [37]. On these bases the trial did not lead to drug approval [37].