Bezafibrate and medroxyprogesterone acetate in resistant and relapsed endemic <scp>B</scp>urkitt lymphoma in <scp>M</scp>alawi; an open‐label, single‐arm, phase 2 study (ISRCTN34303497)

Molyneux, Elizabeth; Merrick, Blair; Khanim, Farhat L.; Banda, Kondwani Joseph; Dunn, Janet A.; Iqbal, Gulnaz; Bunce, Christopher M.; Drayson, Mark T.

doi:10.1111/bjh.12681

Cited by 13 publications

(18 citation statements)

References 9 publications

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“…This study is relevant to the wider context of cancer therapeutics where significant effort is being invested into developing therapeutics that can disrupt fatty acid biosynthesis by interfering with SCD1 due to its apparent anticancer activity (21)(22)(23). To our knowledge, this is the first study to describe clinically available drugs with demonstrable antileukemic and antilymphoma activity in clinical trials (11,12) that target this pathway. …”

Section: Discussionmentioning

confidence: 96%

“…To establish the amount of each compound that came from 13 C D-glucose, the intensity of all the 13 C isotope peaks was summed minus the naturally occurring 13 C intensity from the 12 to generate relative fold changes.…”

Section: D-glucose Tracer Study Data Analysismentioning

confidence: 99%

“…11) and eBL patients (ISRCTN34303497; ref. 12). In vitro, BaP induces intracellular reactive oxygen species (ROS) in tumor cells, which is thought to be important for cell killing (8)(9)(10); however, as yet, we do not have a complete mechanism that fully explains the action of BaP against these diverse hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

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Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

et al. 2015

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The redeployed drug combination of bezafibrate and medroxyprogesterone acetate (designated BaP) has potent in vivo anticancer activity in acute myelogenous leukemia (AML) and endemic Burkitt lymphoma (eBL) patients; however, its mechanism-of-action is unclear. Given that elevated fatty acid biosynthesis is a hallmark of many cancers and that these drugs can affect lipid metabolism, we hypothesized that BaP exerts anticancer effects by disrupting lipogenesis. We applied mass spectrometry-based lipidomics and gene and protein expression measurements of key lipogenic enzymes [acetyl CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and stearoyl CoA desaturase 1 (SCD1)] to AML and eBL cell lines treated with BaP. BaP treatment decreased fatty acid and phospholipid biosynthesis from 13 C D-glucose. The proportion of phospholipid species with saturated and monounsaturated acyl chains was also decreased after treatment, whereas those with polyunsaturated chains increased. BaP decreased SCD1 protein levels in each cell line (0.46-to 0.62-fold; P < 0.023) and decreased FASN protein levels across all cell lines (0.87-fold decrease; P ¼ 1.7 Â 10 À4 ). Changes to ACC1 protein levels were mostly insignificant. Supplementation with the SCD1 enzymatic product, oleate, rescued AML and e-BL cells from BaP cell killing and decreased levels of BaP-induced reactive oxygen species, whereas supplementation with the SCD1 substrate (and FASN product), palmitate, did not rescue cells. In conclusion, these data suggest that the critical anticancer actions of BaP are decreases in SCD1 levels and monounsaturated fatty acid synthesis. To our knowledge, this is the first time that clinically available antileukemic and antilymphoma drugs targeting SCD1 have been reported. Cancer Res; 75(12); 2530-40. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 96%

Section: D-glucose Tracer Study Data Analysismentioning

confidence: 99%

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Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

et al. 2015

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“…W hilst m ale patients may feel hesitant at em barking on a treatm ent regime utilizing a female sex steroid, we have show n these agents to be effec tive in end stage AML [39], and im portantly, w hen taken long term (in excess of 200 weeks) had no associated side effects. In addition, m ore recendy we have dem onstrated the efficacy of the sam e drugs in relapsed and refractory endem ic BL [24]. Thus, the use of these agents has been show n to be effective, w ithout side effects, at both ends of the age spectrum .…”

Section: Discussionmentioning

confidence: 99%

“…More recently, we have established that these agents have marked in vivo anti-lymphoma activity against refractory and relapsed endemic BL [24]. Here we further investigated the potential use of this combination against indolent B-NHL.…”

mentioning

confidence: 98%

Bezafibrate and medroxyprogesterone acetate target resting and CD40L-stimulated primary marginal zone lymphoma and show promise in indolent B-cell non-Hodgkin lymphomas

Hayden

Kussaibati

Cronin

et al. 2014

Leukemia & Lymphoma

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B cell non-Hodgkin lymphomas (B-NHLs) are the most common adult hematological cancers and many remain incurable. Development of chemotherapy regimens is confounded by the prevalence of B-NHL in older, frailer patients and the chemo-protective tumor microenvironment. Although biological therapies such as rituximab have significantly improved outcomes and selective kinase inhibitors are showing promise, the rate of new drug discovery remains disappointing, the treatments expensive and long-term benefits uncertain. An alternative strategy is redeployment of available, inexpensive and non-toxic drugs. Here, we demonstrate the antiproliferative and mitochondrial superoxide (MSO) driven pro-apoptotic activities of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against B-NHL cells, with a bias toward MZL, in the presence and absence of the microenvironmental signal CD40L. Our study is the first to confirm the presence of CD40L within the lymph node of B-NHL and its capacity to drive B-NHL proliferation. These findings implicate BEZ + MPA as a potential therapeutic strategy in B-NHL.

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Single arm phase II trial assessing the safety, compliance with and activity of Bezafibrate and medroxyProgesterone acetate (BaP) therapy against myeloid and lymphoid cancers

Murray

Pratt

Jacob

et al. 2019

Contemporary Clinical Trials Communications

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We previously reported the safety and efficacy of low dose BaP [ B ezafibrate (Bez) a nd Medroxy p rogesterone acetate (MPA)] in 20 acute myeloid leukaemia (AML) patients for whom chemotherapy was not an option. This study provided evidence that BaP had anti-AML activity and improved haemopoiesis; absence of haematological toxicity allowed continuous daily administration. Similarly a previous trial in endemic Burkitt lymphoma demonstrated anti-B cell lymphoma activity of low and high dose BaP again in the absence of toxicity. We conducted a study to further evaluate the safety and activity of high dose BaP therapy in adults with AML (and high risk Myelodysplastic Syndromes (MDS)), chronic lymphocytic leukaemia (CLL) or B-cell Non-Hodgkin Lymphoma (BHNL). Eighteen patients were recruited to the study over 20 months, 16 AML/MDS, 1 CLL, and 1 BNHL. Although MPA was well tolerated throughout the study, only 2 patients were able to tolerate Bez treatment for their whole trial duration, indicating that Bez escalation is not feasible in the setting of adult AML/MDS. Thus there has been no obvious benefit in improved haemopoiesis or overt anti-leukaemia activity from the attempts to escalate BaP dose over previous published studies. Since current therapeutic options in MDS are restricted it may be now of value to continue to evaluate low dose BaP based approaches in low risk MDS rather than AML/high risk MDS. Furthermore, screening of low dose BaP against libraries of other already available dugs may identify an addition to BaP that augments the anti-neoplastic efficacy without significant toxicity.

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Bezafibrate and medroxyprogesterone acetate in resistant and relapsed endemic Burkitt lymphoma in Malawi; an open‐label, single‐arm, phase 2 study (ISRCTN34303497)

Cited by 13 publications

References 9 publications

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

Bezafibrate and medroxyprogesterone acetate target resting and CD40L-stimulated primary marginal zone lymphoma and show promise in indolent B-cell non-Hodgkin lymphomas

Single arm phase II trial assessing the safety, compliance with and activity of Bezafibrate and medroxyProgesterone acetate (BaP) therapy against myeloid and lymphoid cancers

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