PLX51107

P1/2, N=2, Terminated, Hannah Choe, MD | Completed --> Terminated; Sponsor decision

Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.

P1/2, N=2, Completed, Hannah Choe | Recruiting --> Completed | Phase classification: P1b/2 --> P1/2 | N=34 --> 2 | Trial completion date: Dec 2025 --> Sep 2023 | Trial primary completion date: Dec 2024 --> Sep 2023

In a heavily pre-treated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit.

To study pharmacologic Brd4 inhibition in Tet2 KO mice, we utilized PLX51107, a structurally distinct BET inhibitor previously reported on by our laboratory...Our novel inducible double knockout mouse model of CH achieved simultaneous knockout of Brd4 and Tet2, which has never been investigated. Collectively, our data provides rationale for further pre-clinical investigation of BET inhibitors to prevent progression of Tet2 CH.

Objective: Standard of care drugs for rhabdomyosarcoma (RMS), such as vincristine and doxorubicin, have a high systemic toxicity and >70% of high-risk patients develop resistance... ARMS cell lines (RH4, RH30) were treated with BETi compounds (BMS-986158, PLX51107) using a 12-point serial dilution (2.6 nM-10 M)... Functional validation confirmed BETi's potential for in vivo ARMS studies. Ongoing clinical trials of the primary drug candidate, BMS-986158, in childhood cancers increases the likelihood of clinical trial opportunities in RMS. Our metastatic models demonstrate clinical relevance and BETi sensitivity, crucial for addressing the lack of established metastatic ARMS studies.

Since Cisplatin-resistant sublines of UCC (LTTs) are highly dependent on DDR and apoptosis resistance, we characterized response of LTTs and treatment naïve parental cells towards combined treatment with PLX51107 and the PARP inhibitor (PARPi) Olaparib. Applicability of PARPi may be extended to BRCA wild-type cancer patients by episensitation with PLX51107. Thus, this combination could be a promising therapeutic option for UC also for second line treat- ment after chemotherapy.

Conclusion s : Our data indicates that a) PLX51107 has an antitumor effect in CLL cells; b) the combinational treatment of Venetoclax with PLX51107 highly improved the apoptotic effect of single agent treatments. A better understanding of the key signaling pathways for CLL cells' proliferation and survival impacted by BRD4i in combination with Venetoclax would provide a proof-of-concept rationale for studies validating BRD4i as epigenetic approach to target BCR signaling in CLL.

Our data suggests that Venetoclax in combination with PLX51107 exhibits a synergistic effect across a broad range of MCL cell lines. Further elucidation of the mechanism by which PLX51107 and Venetoclax establish synergy is necessary for therapeutic advancement within the field of MCL.

Thus, the goal of this study is to explore the molecular mechanisms behind promising epigenetic inhibitors in RMS, focusing on embryonal RMS, and to test these drugs in vivo in combination with vincristine. Our laboratory obtained a selection of epigenetic compounds from the Ontario Institute of Cancer Research (OICR) and Structural Genomics Consortium (SGC) that mainly target BET (BMS-986158, I-BET151, PLX51107) or HDAC (Apicidin, Domatinostat, Fimepinostat) proteins...Furthermore, the level of apoptosis in this cell line was higher after treatment with PLX51107 than after treatment with the positive control, doxorubicin (Figure 3)... Our data suggest that BET inhibitors may exploit an epigenetic weakness of ERMS, perhaps related to MYC amplification. In the future, we plan to conduct transcriptome assays to explore the mechanism of action of BET inhibitors in ERMS, and in vivo drug combination studies in an ERMS mosaic mouse model and patient-derived xenografts (PDXs).

Pan BET inhibitors (BET-i), such as PLX51107 (Plexxikon Inc.) significantly improve survival in aggressive CLL murine models...Conclusion : Epigenetic-targeted therapies such as BET-i have the potential to alleviate CLL-induced T cell dysfunction while eliminating B-CLL cells and preventing tumor expansion. Future profiling studies are pending to further illuminate how BET proteins regulate immune function in CLL.

Median prior # therapies = 3 [1-9]; 97% had prior HMA therapy; 84% had prior venetoclax (VEN).17 (46%) pts had prior stem cell transplant (SCT); 7 of whom were on concurrent active immunosuppressive therapy for GVHD prophylaxis at time of enrollment and continued on study (n=6 tacrolimus; n=1 sirolimus). Future directions may include investigation of novel BETi combinations in VEN-naïve pts, further investigation into high-risk subsets of pts with chr 3 abnl/ EVI1/MECOM rearrangements, RUNX1 , and RAS -family mutated pts, and further clinical/translational investigation of BETi activity in leukemia cutis/skin lesions in myeloid malignancies. ClinicalTrials.gov Identifier: NCT04022785.

Using potent and selective BET inhibitors Plexxikon-51107 and -2853 (PLX51107 and PLX2853), we show that BET inhibition significantly improves survival and reduces disease progression in murine models of acute GVHD without sacrificing the beneficial graft-versus-leukemia response. Our findings identify a role for BET proteins in regulating the IL-23R/STAT3/IL-17 pathway. Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial.

These data provide the scientific rationale for a clinical trial of a BET plus FLT3 inhibitor for the treatment of relapsed/refractory FLT3-ITD AML. A clinical trial of PLX51107 as monotherapy in patients with different malignancies is underway and will be reported separately.

Together, our data suggest that intermittent inhibition of BET proteins may improve the duration of responses following BRAFi/MEKi treatment in BRAF-mutant melanoma.

In this study, we investigated the preclinical activity of two BRD4i, AZD5153 and PLX51107, and their cooperative role with the BCL2 inhibitor venetoclax and BTK inhibitor ibrutinib in CLL. Modulation of BCL-2 family members following BRD4 inibition could play a role in the synergistic activity observed in our studies. A better understanding of the key signaling pathways involved in proliferation and survival of CLL cells impacted by BRD4i in combination with venetoclax and ibrutinib would provide a proof-of-concept rationale for studies validating BRD4i as epigenetic approach to target BCR signaling in CLL.

Taken together, these data suggested that blocking of BRDT by PLX51107, INCB054329 or BRDT knockdown suppressed the growth of RCC via decreasing eIF4EBP1, thereby leading to decreased c‑myc transcription levels. Considering the regulatory function of BET proteins in gene transcription, the present study suggested that there is a novel mechanism underlying eIF4EBP1 regulation by BRDT, and subsequently decreased c‑myc in RCC, and further identified a new approach by regulating eIF4EBP1 or c‑myc for enhancing BRDT‑targeting RCC therapy.

Here we characterize the responses of aggressive MYC-driven lymphomas to 2 nonbenzodiazepine BETi: PLX51107 and PLX2853. Consequently, coadministration of BETi and ABT199/venetoclax restored cell death and in vivo therapy. Collectively, these data identify BIM-dependent apoptosis as a critical mechanism of action for this class of BETi that, via coadministration of BH3 mimetics, can deliver effective tumor control in DLBCL.

We evaluated the efficacy in the treatment of ATC of a novel BET inhibitor, PLX51107 (PLX), currently in clinical trials for other solid tumors and hematologic malignancies, alone or combined with a MEK inhibitor, PD0325901(PD). These findings indicate that combined treatment of BET and MEK-ERK inhibitors was more effective to treat ATC than single targeted treatment. Synergistic suppression of MYC transcription via collaborative actions on chromatin modifications suggested that targeting epigenetic modifications could provide novel treatment opportunities for ATC.

In multiple tumor models (EMT6, 4T1, LLC, and C26) Brd4 inhibitors, both experimental (JQ1) and those in clinical development (PLX51107 and PLX2853) significantly reduced the abundance of total, PMN, and M-MDSC subsets within the tumor and spleen as measured by flow cytometry and IHC (p< 0.05). Finally, depletion of MDSCs in vivo with PLX51107 significantly enhanced the efficacy of anti-PDL1 therapy as compared to either agent alone (p< 0.05 in EMT6, 4T1, and LLC tumor models). These results identify Brd4 and the TXNIP/ASK1 apoptosis pathway as novel regulators of MDSC survival, and provide evidence to further investigate Brd4 inhibitors in combination with immune based therapies for solid tumors.

Importantly, PLX51107 delayed the growth of tumors that progressed on anti-PD-1 therapy; a response associated with decreased Cox2 levels, decreased PD-L1 expression on non-immune cells and increased intratumoral CD8+ T cells. Thus, next generation BETi represent a potential first-line and secondary treatment strategy for metastatic melanoma by eliciting effects, at least in part, on anti-tumor CD8+ T cells.