Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for double hit and triple hit B-cell lymphomas

Cinar, Munevver; Rosenfelt, Fred; Rokhsar, Sepehr; Lopategui, Jean; Pillai, Raju; Cervania, Melissa; Pao, Andy; Cinar, Bekir; Alkan, Serhan

doi:10.1016/j.leukres.2015.04.003

Cited by 26 publications

(17 citation statements)

References 36 publications

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“…MYC, BCL-2 and/or BCL-6 overexpression due to genetic rearrangements are key features of double-hit or triple-hit lymphoma (DHL/THL), aggressive forms of B cell lymphoma with poor survival rates and no truly effective treatment options (67, 68). Venetoclax has been shown to induce cell death in DHL cell lines Sc-1 and Ocl-LY18, the RL cell line and primary human DHL cells that overexpress BCL-2.…”

Section: Identifying Sensitive Tumor Types and Likely Respondersmentioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax.

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Section: Identifying Sensitive Tumor Types and Likely Respondersmentioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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“…Whether features such as morphologic classification, BCL2 expression, or type of MYC translocation partner may mitigate the adverse prognosis in “double‐hit” and “triple‐hit” lymphomas is controversial . An expanding literature exists regarding predictive biomarkers, therapeutic regimen recommendations, and precision tailored approaches to “double‐hit” and “triple‐hit” lymphomas . Novel treatment strategies with small molecule inhibitors may hold hope for newly diagnosed individuals, and combination therapy with pembrolizumab and lenalidomide has been reported to induce remission in refractory disease .…”

Section: Discussionmentioning

confidence: 99%

“Triple hit” lymphomas: A retrospective cytology case series of an uncommon high grade B‐cell malignancy with C‐MYC, BCL‐2 and BCL‐6 rearrangements

Eldessouki

Hanley

Hamadeh

et al. 2018

Diagnostic Cytopathology

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The Revised fourth Edition World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues suggests novel categories, including "high grade B-cell lymphoma with MYC and BCL2 and BCL6 gene rearrangements." These diseases are known colloquially as "double hit" and "triple hit" lymphomas. The "first-hit" in these cases is the harboring of a MYC rearrangement. Concurrent derangements of BCL2 and BCL6 can be the "second-hit" or "third-hit." To our knowledge, this is the first report of "triple-hit" lymphomas in cytology specimens. The files of the Cleveland Clinic (January 2007 through December 2017) were searched for all "triple hit" lymphomas. Four cases met inclusion criteria (cytology slides in files and histologically confirmed "triple hit" lymphoma). All slides were reviewed. The mean age was 65 years, with a male predominance. All patients presented at advanced stage and showed progressive disease despite therapy. FISH studies (histologic sections) confirmed translocations of MYC (8q24), BCL2 (18q21) and BCL6 (3q27) in all patients. All cases were characterized by high cellularity, dispersed cells, presence of stripped nuclei, lymphoglandular bodies, apoptotic bodies, cytomegaly, nucleomegaly, nuclear envelope irregularities, macronucleoli (most often single), recognizable mitoses and presence of cytoplasmic vacuoles (variable). The WHO recommends that all large B-cell lymphomas be investigated using cytogenetic or molecular techniques. Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for triple hit lymphomas, and an expanding literature exists regarding predictive biomarkers and therapeutic regimens. It is our intention to raise awareness of this uncommon mature B-cell neoplasm within the cytodiagnostic community.

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“…Of course classically, BCL6 has been widely studied in the context of B-cell lymphoma (35) and its connection to TGFβ resistance (36). In particular, for a subgroup of lymphoma cases, known as “double-hit lymphoma”, BCL6 and MYC aberrations together are considered as prognostic factors (37). Interestingly, we find the analogous result that MYC regulates BCL6 expression in a subset of NSCLC cell lines.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers

et al. 2017

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Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, K-RAS, and MYC—oncogenic alterations commonly found in non-small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1 and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 up-regulation and another with SMAD2/3 down-regulation. Treatment with a STAT3 inhibitor eliminated the up-regulated STAT3 subpopulation, but left a large surviving subpopulation with down-regulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes and tumor suppressors may provide a potent way to defeat intra-tumor heterogeneity.

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Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for double hit and triple hit B-cell lymphomas

Cited by 26 publications

References 36 publications

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

“Triple hit” lymphomas: A retrospective cytology case series of an uncommon high grade B‐cell malignancy with C‐MYC, BCL‐2 and BCL‐6 rearrangements

Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers

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