Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas

Koch, Raphael; Christie, Amanda L.; Crombie, Jennifer; Palmer, Adam C.; Plana, Deborah; Shigemori, Kay; Morrow, Sara; Scoyk, Alexandria Van; Wu, Wen-Chao; Brém, Elizabeth; Secrist, J. Paul; Drew, Lisa; Schuller, Alwin G.; Cidado, Justin; Letaï, Anthony; Weinstock, David M.

doi:10.1182/blood-2018-07-865527

Cited by 44 publications

(43 citation statements)

References 30 publications

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“…Kaplan-Meier test was used for the survival rate analysis, and the data were statistically analyzed using log-rank (Mantel-Cox) test. The Bliss independence model was adapted to assess additive vs. synergistic activity of DT2216 + ABT199 in the DFTL-28776 TCL PDX mice as we previously described [8]. p < 0.05 was considered statistically significant.…”

Section: Discussionmentioning

confidence: 99%

“…The spleens were harvested from the mice for immunoblotting analyses of Bcl-xL, Bcl-2, and Mcl-1 expression. To assess additive vs. synergistic activity of DT2216 + ABT199 in DFTL-28776 TCL PDX mice, the Bliss independence model [17] was adapted to survival analysis as previously described [8]. A second study was performed to further characterize the effects of ABT199 and/or DT2216 on DFTL-28776 T-PLL PDX, in which previously frozen DFTL-28776 cells were used for the xenografts.…”

Section: Dftl-28776 T Cell Prolymphocytic Leukemia (T-pll) Pdx Model mentioning

confidence: 99%

“…Using the BH3 profiling assay, our previous studies revealed that a fraction of human TCL cell lines are exclusively dependent on Bcl-xL for survival and are highly sensitive to Bcl-xL-specific and dual Bcl-2/Bcl-xL inhibitors [8]. We tested four Bcl-xL-dependent TCL cell lines (i.e., MyLa, MJ, MAC2A, and L82), and all of them expressed high levels of Bcl-xL and low levels of Bim ( Fig.…”

Section: Dt2216 Selectively Kills Bcl-xl-dependent Tcl Cell Lines By mentioning

confidence: 99%

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DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas

Koch

Budamagunta

et al. 2020

J Hematol Oncol

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Background: Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patientderived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia. Methods: We have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TCLs via testing its anti-TCL activity in vitro using MTS assay, immunoblotting, and flow cytometry and anti-TCL activity in vivo using TCL cell xenograft and PDX model in mice. Results: The results showed that DT2216 selectively killed various Bcl-xL-dependent TCL cells including MyLa cells in vitro. In vivo, DT2216 alone was highly effective against MyLa TCL xenografts in mice without causing significant thrombocytopenia or other toxicity. Furthermore, DT2216 combined with ABT199 (a selective Bcl-2 inhibitor) synergistically reduced disease burden and improved survival in a TCL PDX mouse model dependent on both Bcl-2 and Bcl-xL. Conclusions: These findings support the clinical testing of DT2216 in patients with Bcl-xL-dependent TCLs, both as a single agent and in rational combinations.

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Section: Discussionmentioning

confidence: 99%

Section: Dftl-28776 T Cell Prolymphocytic Leukemia (T-pll) Pdx Model mentioning

confidence: 99%

Section: Dt2216 Selectively Kills Bcl-xl-dependent Tcl Cell Lines By mentioning

confidence: 99%

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DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas

Koch

Budamagunta

et al. 2020

J Hematol Oncol

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“…When sufficiently engrafted, mice were treated for four cycles of AZD4573 and monitored daily for clinical signs of disease and humanely euthanized when they reached a clinical endpoint. Annexin V was assessed in human CD45 þ tumors isolated from peripheral blood 6 hours after the second day 2 dose as previously described (23).…”

Section: T-cell Lymphoma Patient-derived Xenograftmentioning

confidence: 99%

AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells

Cidado

Boiko

Proia

et al. 2020

Clinical Cancer Research

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135

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Purpose: Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many cancers. Multiple nonselective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573. Experimental Design: The antitumor activity of AZD4573 was determined across broad cancer cell line panels in vitro as well as cell line-and patient-derived xenograft models in vivo. Multiple approaches, including integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacologic comparisons, were employed to further understand the major mechanism driving AZD4573 activity and to establish an exposure/ effect relationship. Results: AZD4573 is a highly selective and potent CDK9 inhibitor. It demonstrated rapid induction of apoptosis and subsequent cell death broadly across hematologic cancer models in vitro, and MCL-1 depletion in a dose-and time-dependent manner was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. This pharmacodynamic (PD) response was also observed in vivo, which led to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses both as monotherapy or in combination with venetoclax. This understanding of the mechanism, exposure, and antitumor activity of AZD4573 facilitated development of a robust pharmacokinetic/PD/efficacy model used to inform the clinical trial design. Conclusions: Selective targeting of CDK9 enables the indirect inhibition of MCL-1, providing a therapeutic option for MCL-1dependent diseases. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematologic malignancies (clinicaltrials.gov identifier: NCT03263637). See related commentary by Alcon et al., p. 761

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“…Combination of venetoclax with the purine analog pentostatin was tested in one r/r T-PLL case, resulting in a CR [64]. Besides targeting BCL2, inhibition of the anti-apoptotic MCL1 represents another strategy to be further investigated in T-PLL [65].…”

Section: Antagonists Of Bcl2 Family Moleculesmentioning

confidence: 99%

Advances and Perspectives in the Treatment of T-PLL

Braun

Jan

Wahnschaffe

et al. 2020

Curr Hematol Malig Rep

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Purpose of Review T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumabbased induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies. Recent Findings Alemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CART cell therapy are at the stage of pre-clinical assessments of activity and feasibility. Summary The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-inhuman results in T-PLL, and urgently have to be transferred to systematic clinical testing.

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Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas

Cited by 44 publications

References 30 publications

DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas

DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas

AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells

Advances and Perspectives in the Treatment of T-PLL

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