In an effort to find novel drug targets for triple negative breast cancer (TNBC), Phoenix Molecular Designs (PhoenixMD) has developed PMD-026, the first orally bioavailable small molecule inhibitor targeting RSK (p90 ribosomal S6 kinase). RSK2 was identified as the most important kinase for the growth of TNBC compared to other breast cancer subtypes through siRNA functional screens. The RSK family of kinases are a convergence point in the EGFR, MAPK and PDK-1 pathways. They are implicated in the regulation of transcriptional and translational signalling, which promotes the growth and metastasis of invasive breast cancers. In breast cancer, they activate a number of transcription factors through phosphorylation events, including the estrogen receptor and the Y-box binding protein-1 (YB-1), the latter of which has been shown to drive the development of TNBC in mice. RSK2 is an ideal molecular target due to broad spectrum tumor dependency, despite the known heterogeneity within TNBC. PMD-026 demonstrates high specificity for the four RSK isoforms in vitro (IC50 0.7 -2 nM), with good selectivity in a kinome-wide counter screen. PMD-026 is active across a heterogeneous panel of TNBC cell lines in vitro under anchorage independent (IC50 0.2 - 6.2 µM) and dependent growth conditions (IC50 1.8 - 8.4 µM). Further, it synergizes with chemotherapies such as paclitaxel and doxorubicin in breast cancer cell lines in vitro. PMD-026 induces apoptosis, as indicated by increased expression of cleaved PARP, and induces changes in intracellular pathway signaling, with consistent dose-dependent decreased expression of pYB-1, a downstream target of RSK. PMD-026 demonstrates in vivo efficacy in several mouse xenograft tumor models of TNBC, when administered as a single agent, with significant tumor growth inhibition (TGI) and regression measured in MDA-MB-231 (72% TGI, p ≤ 0.001) and MDA-MB-468 xenografts (73% regression, p ≤ 0.001), respectively. PMD-026 also inhibits the growth of a PDx TNBC tumor model in vivo in combination with paclitaxel (80% TGI, p ≤ 0.001). A dose-dependent decrease in pYB-1 expression in the treated tumors is observed, indicative of consistent target engagement in vivo. Through these studies, we are able to show that PMD-026 is active across tumors models that have mutant BRCA1/2 and/or express PDL-1, providing a potential alternative treatment strategy when therapies such as PARP inhibitors or TECENTRIQ fail. In GLP toxicology studies, PMD-026 did not cause any apparent cardiotoxicity, neutropenia or ocular toxicity in mice and dogs, setting RSK inhibitors apart from other inhibitors targeting kinases in the MAPK signaling pathway. Lastly, we developed a companion diagnostic (CDx) and determined that RSK2 is activated in 85% of TNBC. Taken together, we have an Rx/Dx solution for TNBC predicated on functional dependency. PMD-026 is a first-in-class RSK inhibitor purpose built for the treatment of TNBC, which provides a unique opportunity to deliver a new treatment option for patients in our Phase1/1b clinical trial. Citation Format: Sandra E. Dunn, Aarthi Jayanthan, My-my Huynh, Erik Flahive, Mary Rose Pambid, Andrew Dorr, Gerrit Los. PMD-026, a first-in-class oral p90 ribosomal S6 kinase (RSK) inhibitor for triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-10.
PMD-026 is a first in class, reversible, oral small molecule inhibitor of p90 ribosomal S6 kinase (RSK), a kinase family activated by the MAPK and PDK-1 pathways, which regulate substrates involved in cancer cell proliferation and drug resistance. Specifically, RSK2 has been identified as a major driver in breast cancer (BC). In preclinical studies and a Phase I clinical trial in metastatic BC, PMD-026 demonstrated a good safety profile, making it an attractive candidate for combinations with standard of care therapies. Here in we show that RSK2 is activated in 87% of triple negative breast cancer (TNBC), as well as in other subtypes (80% of ER+/PR+ and 81% of HER2+). In a screen of 28 BC cell lines across a broad mutational spectrum, PMD-026 induced apoptosis in most of the models. Next, to determine the role of PMD-026 in the context of conventional BC treatment, we combined it with standard of care chemotherapies fulvestrant, paclitaxel, or doxorubicin, in vitro and in vivo. PMD-026 synergized with fulvestrant, with combination drug index (CDI) values ranging from 0.73 - 0.92 in the HR+ cell line MCF-7. Likewise, PMD-026 synergized with paclitaxel and doxorubicin in TNBC cell lines with CDI values ranging from 0.40 - 0.84 and 0.58 - 0.92 for paclitaxel and doxorubicin, respectively. Consistent with in vitro screening data, PMD-026 synergized with paclitaxel in vivo in the SUM149PT TNBC xenograft model after 38 days of treatment. The combination inhibited tumor growth by 66% (P < 0.0001), whereas paclitaxel and PMD-026 as single agents inhibited tumor growth by 22% (P = 0.3051) and 41% (P = 0.0041), respectively. The synergy of this combination was further supported by a CDI value of 0.75. Treatment among the groups was well tolerated with no changes in body weight observed. Similarly, the combination of PMD-026 and paclitaxel was synergistic in SUM149PT(48 days, CDI: 0.78) and MDA-MB-231 (28 days, CDI: 0.66) xenografts and additive in a PDx model of metastatic TNBC (18 days, CDI: 0.96), resulting in improved survival. To address the safety of combining PMD-026 and paclitaxel, drug-drug interactions (DDI) were assessed. In cytochrome P450-mediated in vitro metabolism assays, PMD-026 showed weak inhibition of Cyp2C8 and Cyp3A4, the main enzymes responsible for paclitaxel metabolism. To understand whether PMD-026 might alter the metabolism of paclitaxel, this potential DDI was assessed in vivo. Pharmacokinetic analysis of PMD-026 (7 days repeat dosing) combined with paclitaxel (8 mg/kg IV dose Day 1 and Day 7) was evaluated in CD-1 mice, however, PMD-026 did not change the absorption, distribution, or blood levels of paclitaxel. Together, these data support adding PMD-026 to standard of care therapies in breast cancer, as they have demonstrated synergy. In particular, PMD-026 is synergistic with paclitaxel in multiple TNBC models, in which it improves efficacy without added toxicity. Citation Format: Aarthi Jayanthan, My-my Huynh, Jangsoon Lee, Gerrit Los, Lambert Yue, Mary Rose Pambid, Naoto T. Ueno, Sandra E. Dunn. PMD-026, a first in class oral RSK inhibitor, demonstrates synergy when combined with standard of care in breast cancer tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1038.
Background: Metastatic breast cancer (mBC) remains an aggressive disease with limited durable treatment options; the worst prognosis among the breast cancer subtypes is typically seen in metastatic triple-negative breast cancer (mTNBC). Given that unmet need, we sought to identify an actionable molecular target to combat mTNBC. Promising preclinical activity identified p90 ribosomal s6 kinase 2 (RSK2) as a key kinase in mTNBC. PMD-026 is a potent, oral, small molecular RSK inhibitor with high selectivity for the RSK2 isoform. RSK is a major convergence point in the important MAPK and PDK-1 signaling pathways, which drive TNBC cell survival, proliferation, and drug resistance. Methods: The primary aim of this single-arm, open-label, first-in-human, phase 1/1b study (NCT04115306) is to evaluate the safety of single agent PMD-026 in patients with mBC. Secondary endpoints are clinical activity, pharmacokinetics (PK) and correlative biomarker expression on tumor specimens. Patients are dosed orally once or twice daily in 21-day cycles with measures to adapt the dosing schedule based on the PK data, as needed. In dose escalation, patients must have mBC with evaluable or measurable disease by RECIST v1.1. In dose expansion, patients must have mTNBC with measurable disease by RECIST v1.1. Patients must have progressed on or after standard of care therapy. Tumor tissue is required to retrospectively correlate RSK2 activity with clinical outcomes via immunohistochemistry using a CAP/CLIA certified companion diagnostic (CDx). Results: Twelve mBC patients (ER+ mBC n=5, mTNBC n=7) who have failed standard chemotherapy as well as targeted therapies such as CDK4/6 inhibitors and immunotherapies have been enrolled to date. Patients have been treated in escalating cohorts of 25, 50, 100, 200, 400 (200 q12) or 600 mg (300 q12) of PMD-026 administered orally daily. At 400 mg the dose schedule was changed from daily to q12 hrs based on PK results to optimize drug exposure over a 24-hr timeframe in patients. The PK of PMD-026 showed linear exposure and a high volume of distribution. The AUC was ~9100 hr*ng/ml on Day 1 when PMD-026 was dosed at 200 mg qd demonstrating high exposure. In addition, when dosed at 200 mg q12 hrs, PMD-026 serum levels approached the preclinically established desired level of 1 µM over 24 hrs. In the 200 mg q12 hrs cohort, adverse events consisted of G2 GERD (n=1) and G2 neutropenia (n=1). Initial signs of activity were observed as CT-identified necrosis in a neck node metastasis (n=1) and transient decrease in CA 27-29 (n=1). While the 200 mg q12 hrs dose was generally well-tolerated, there were 2 dose limiting toxicities at 300 mg q12 hrs including syncope (n = 1) and vomiting with dehydration leading to reversible acute kidney injury (n = 1). To further understand the patient population, RSK2 activation was assessed in tumor samples from all patients. RSK2 was activated in all of the tumors and the H-Score ranged from 110 to 198 using the CDx platform. Conclusions: Preliminary evidence indicates that PMD-026 is well-tolerated at dose levels up to 200 mg q12 with initial signs of activity; pharmacokinetics showed good linear exposure. Updated safety, clinical activity, pharmacokinetic and biomarker analyses will be presented; target accrual for Phase 1b Expansion is approximately 20 mTNBC patients. (clinicaltrials.gov NCT04115306). Citation Format: Murali Beeram, Judy S. Wang, Pavani Chalasani, Lida Mina, Amita Patnaik, Mary Rose Pambid, Aarthi Jayanthan, My-my Huynh, Gerrit Los, Sandra E. Dunn, F. Andrew Dorr. A first-in-human Phase 1/1b multicenter, open-label dose escalation study to assess safety and tolerability of PMD-026, a first-in-class oral RSK inhibitor, in metastatic breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-33.
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