Abstract B031: MetAP2 inhibition by evexomostat (SDX-7320) decreases EZH2 and c-Myc and significantly prolongs survival in enzalutamide-resistant and neuroendocrine prostate cancer models
Results show that inhibition of METAP2 with SDX-7320 is a novel approach to treat ARPI-resistant as well as aggressive forms of prostate cancer warranting immediate clinical translation.
Abstract
Androgen receptor pathway inhibitors (ARPIs) improve outcomes for patients with mCRPC. However, development of resistance to ARPIs is a significant clinical issue associated with the emergence of aggressive variant prostate cancer (AVPC), and consequently there is an urgent need for novel, AR pathway-independent therapies. Expression of the metalloprotease methionine aminopeptidase 2 (METAP2) has been correlated with increased mCRPC aggressiveness: high expression was reported in dedifferentiated phenotypes, including NEPC/AVPC. METAP2 regulates protein translation, post-translational modifications and has a clinically validated role inhibiting angiogenesis. METAP2 also has tumor-specific functions coordinating plasticity, vascular mimicry, and hypoxia response. Evexomostat (SDX-7320) is a prodrug of a highly potent, novel METAP2 inhibitor which has completed a phase I safety study in late-stage cancer patients (NCT02743637) and is currently being clinically investigated in patients with metastatic breast cancer (NCT05570253, NCT05455619). It was hypothesized that SDX-7320 would demonstrate anti-tumor efficacy in non-clinical prostate cancer cell-derived xenograft and patient-derived xenograft (PDX) models of ARPI-resistant CRPC and AVPC.
SDX-7320 (12 or 8 mg/kg, subcutaneous dosing, every four days) was tested in NSG mice with LNCaP xenografts in intact, castrated, and CRPC models. SDX-7320 treatment was also evaluated in LuCaP35.CR PDX xenografts in castrate mice alone as well as in combination with enzalutamide following development of resistance to enzalutamide. SDX-7320 was also tested in the LTL545, LUCAP49 and LTL331R (AR-negative, NE-positive) models of AVPC. Tumor growth was assessed and following dissection subsequently analyzed for transcriptomic (RNAseq), protein (Western blot) or histological differences (H&E staining, CD34 IHC).
SDX-7320 treatment significantly reduced tumor volume in every model and at every PC stage investigated, alone and in combination with enzalutamide (in enzalutamide-resistant tumors), as well as in the LTL545, LUCAP49 and LTL331R AVPC models. Reduced angiogenesis marker CD34 staining was observed in all tumors from SDX-7320-treated mice. Survival of mice treated with SDX-7320 was significantly enhanced, regardless of model phenotype. Downstream analyses of bulk RNAseq and proteomics showed model-specific changes to plasticity regulators c-Myc and the enhancer of zeste homolog 2 (EZH2) indicating an effect of METAP2 inhibition on prostate cancer cellular differentiation.
These results show that inhibition of METAP2 with SDX-7320 is a novel approach to treat ARPI-resistant as well as aggressive forms of prostate cancer warranting immediate clinical translation. Building upon the non-clinical data in models of AVPC presented here, combined with the body of clinical experience with SDX-7320 in past and ongoing clinical trials, planning is underway to conduct a pilot clinical trial with SDX-7320 in men with AVPC.
Peter Cornelius, Devina Laurencia, Jennifer H. Gunter, Anja Rockstroh, Benjamin A. Mayes, Pierre Dufour, Bradley J. Carver, James M. Shanahan, Colleen C. Nelson. MetAP2 inhibition by evexomostat (SDX-7320) decreases EZH2 and c-Myc and significantly prolongs survival in enzalutamide-resistant and neuroendocrine prostate cancer models [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B031.
The epigenetic regulator protein arginine methyltransferase 5 (PRMT5) is aberrantly overexpressed in triple-negative breast cancer (TNBC) and represents a promising therapeutic target. Currently reported PRMT5-targeting PROTAC degraders (MS4322 and MS115) are both derived from a tetrahydroisoquinoline scaffold. These compounds require treatment for more than five days to exert effective antiproliferative activities, and no in vivo antitumor efficacy has been reported. To address these limitations, we adopted the carbazole-based PRMT5 inhibitor PJ-68, which features a lower molecular weight and a more accessible linker attachment site. Herein, we reported a series of novel PRMT5 degraders with carbazole scaffold. The representative compound YZ-17 degraded PRMT5 (DC50 = 2.2 μM in HCC1806 and 3.3 μM in HCC1937 cells) and its adaptor protein MEP50 (DC50 = 2.0 μM and 2.9 μM, respectively) within 24 h. YZ-17 also suppressed PRMT5-mediated symmetric dimethylarginine (sDMA) modification and colony formation, induced G1 phase cell cycle arrest, and displayed favorable antiproliferative activities across several TNBC cell lines (IC50 = 2.6 - 3.7 μM). Importantly, YZ-17 showed in vivo efficacy in an HCC1806 xenograft model, achieving a tumor growth inhibition (TGI) of 44.12% at 30 mg/kg (i.p., every other day) without obvious toxicity. Collectively, YZ-17 represents a structurally novel PRMT5 degrader with rapid onset of action, effective in vitro and in vivo anti-TNBC activity, offering a distinct chemical tool for further functional studies of PRMT5.
Yu-Zhan Li, Yaxun Guo, Dazhao Mi et al.· European journal of medicina...· 0 citations
Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge. Next-generation protein arginine methyltransferase 5 (PRMT5) inhibitors show promising clinical results in a subset of PDACs with codeletion of the tumor-suppressor CDKN2A and the methylthioadenosine phosphorylase (MTAP) gene, but resistance limits their efficacy. Our study suggests that compensatory spliceosomal reprogramming contributes to adaptation to PRMT5 inhibition. Through comprehensive molecular profiling, we demonstrate that PRMT5 inhibitors induce upregulation of RNA-binding proteins, including RNA-binding protein 39 (RBM39). We investigated whether this response could be therapeutically leveraged by combining PRMT5 inhibition with indisulam-mediated RBM39 degradation, which yielded synergistic activity in cellular model systems. The combination strategy significantly enhanced apoptotic cell death and suppressed tumor outgrowth in resistance assays compared with single-agent treatments. Multiomics analysis revealed concomitant suppression of DNA repair and metabolic pathways. Collectively, our work support spliceosomal rewiring as a candidate adaptive response to PRMT5 inhibition and nominates RBM39 as a candidate therapeutic vulnerability, thereby supporting further evaluation of dual targeting of the splicing machinery. Significance: Our study suggests that compensatory spliceosomal reprogramming occurs in response to PRMT5 inhibition. We investigated this vulnerability by combining PRMT5 inhibition with indisulam-mediated RBM39 degradation, which yielded synergistic antitumor activity in selected cellular PDAC models.
Valentina Spielmann, Jonas Buchloh, Selen Selcen et al.· Cancer Research Communicatio...· 0 citations
A novel metabolic-epigenetic mechanism whereby lactate modulates hepatocellular carcinoma sensitivity to targeted therapies through histone lactylation is delineated and suggests AARS1-H4K12la-RAPGEF3 axis may serve as an interventional target to overcome targeted drug resistance, offering a promising strategy to enhance clinical outcomes in HCC patients.
Tanlun Zeng, Wanwan Zhu, Guanqun Sun et al.· Cell Death and Disease· 1 citation
Cancer cells maintain their fitness by developing survival adaptations that foster escape from intrinsic and extrinsic mechanisms of cell death in conditions of stress. Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) is a lipid kinase associated with poor outcomes in multiple tumors including colorectal cancer (CRC), pancreatic, and breast cancer (Llorente et. al). PIP4K2C regulates local pools of PI(4,5)P2 through a catalytic-independent mechanism and is co-opted by cancer cells to increase their fitness by adapting to metabolic stress and evading immune surveillance. (Wang et al.). We have developed LRK-4189, an orally bioavailable, selective degrader of PIP4K2C with sub- nanomolar potency in primary human cells. LRK-4189-mediated degradation of PIP4K2C leads to intrinsic cell death and upregulation of the STAT1 pathway and signaling in microsatellite stable colorectal cancer (MSS CRC) cells. Treatment of human primary spheroids derived from tumor resections of MSS-CRC patients leads to increased tumor killing and down-modulation of key oncogenic transcriptional pathways. In a recent Phase 1 study in healthy volunteers, LRK-4189 demonstrated safety and tolerability as well as positive proof-of-mechanism with profound degradation of PIP4K2C in peripheral PBMC following a single oral dose.
Degradation of PIP4K2C in tumors leads to modulation of key pro-tumorigenic pathways and upregulation of cytokines, chemokines, and stress-associated receptors. Emerging data from primary patient samples informing both translation and mechanism of action will be discussed. In addition, new in vivo data supporting expansion into other cancers will be highlighted.
Collectively, our results demonstrate that PIP4K2C is conditionally essential under settings of metabolic stress, where its loss induces immunogenic cell death. Clinical studies with LRK-4189 are ongoing with enrollment of cancer patients planned in 2026.
1. Llorente et. al. Nat. Rev. Cancer 2025 2. Wang DG et al. Cell Rep. 2019
Krista B. Goodman, Eva d'Hennezel, Morgan O'Shea, Guosen Ye, Andrew Good, Melvyn Chow, Julie Arnold, Lilly Ein, Sydney Alnemy, Erica Dube, Mike Perricone, Phillipa Graham, Alice Bexon, Catherine Sabatos-Peyton. Clinical development and mechanism of action of LRK-4189, a first-in-class degrader of the lipid kinase PIP4K2C [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B042.
Krista Goodman, Eva B. d'Hennezel, Morgan B. O'Shea et al.· Clinical Cancer Research· 0 citations
Abstract Background Renal cell carcinoma (RCC) is characterized by an immunogenic tumor microenvironment and frequent activation of angiogenic pathways. Therefore, combining immune checkpoint blockade with VEGF pathway inhibition is a rational therapeutic approach. PF‑08634404 is an investigational anti–PD‑1 and anti‑VEGF bispecific antibody that effectively binds both targets. PF‑08634404 uses a tetravalent (2 + 2) structure that enables binding cooperativity between PD-1 and VEGF-A, increasing the avidity for and functional inhibition of PD-1 and resulting in enhanced target engagement. This enhancement differentiates PF‑08634404 from combinations of separate PD‑1 and VEGF inhibitors. PF‑08634404 has shown promising clinical activity in patients with non-small cell lung cancer (NSCLC) or colorectal cancer (CRC), with no dose-limiting toxicities observed up to 45 mg/kg Q3W, highlighting the wide therapeutic margin. Here, we present preclinical data demonstrating high-affinity binding to and functional inhibition of both PD‑1 and VEGF‑A by PF‑08634404, including evidence of VEGF‑mediated cooperative binding. Methods Assays include: 1) flow cytometry to measure binding affinity on PD-1–expressing cells; 2) size exclusion chromatography to measure PF-08634404/VEGF-A multimerization; 3) flow cytometry using pH dye to assess internalization of cell surface PD-1/PF-08634404 complexes; 4) reporter cell assay to determine PD-1 signal blockade; 5) surface plasmon resonance (SPR) to measure affinity for soluble VEGF-A; and 6) in vitro proliferation assays to examine inhibition of VEGF-induced proliferation. Results PF‑08634404 binds PD‑1 and VEGF‑A with sub‑nanomolar affinity and can engage both targets simultaneously. Its affinity for soluble VEGF‑A is approximately 30-fold and 60-fold higher than that of ivonescimab and bevacizumab, respectively, resulting in deeper and more potent VEGF inhibition in vitro. Consistent with the bispecific mechanism, PF‑08634404 multimerizes in the presence of VEGF‑A, increasing avidity for PD‑1 (>100-fold), promoting rapid internalization of PD‑1, and enhancing functional PD‑1 inhibition (>10-fold). Conclusions Collectively, these encouraging preclinical data that define the core mechanistic features of PF‑08634404, the preliminary safety and antitumor activity, and the importance of targeting PD-(L)1 and VEGF support the investigation of PF‑08634404 in pivotal trials across multiple tumor types, including RCC. A phase 1b/2 study (Symbiotic-GU-08) in patients with newly diagnosed advanced or metastatic RCC is being conducted to evaluate the efficacy and safety of PF‑08634404, either as monotherapy or in combination with ipilimumab (anti–CTLA‑4) or axitinib (VEGF tyrosine kinase inhibitor) (NCT07227415). Symbiotic-GU-08 enables a novel “tripartite” approach to frontline treatment of RCC through combination therapy. PD‑1 blockade in combination with ipilimumab-mediated CTLA‑4 inhibition produces complementary immune activation. Adding PF‑08634404’s VEGF neutralization to a PD‑1/CTLA‑4 backbone would be expected to further enhance the immune response by reducing VEGF-driven immunosuppression and abnormal vasculature and by improving T‑cell infiltration and function. PF‑08634404 in combination with axitinib, a potent VEGFR1–3 tyrosine kinase inhibitor, creates dual VEGF-pathway blockade on top of PD‑1 inhibition. This strategy could more thoroughly shut down tumor angiogenesis, in addition to leveraging the immunomodulatory effects of axitinib that may further complement PD‑1 blockade. PF‑08634404 has demonstrated clinical proof of concept in other cancers. Together, these data provide a strong scientific rationale to evaluate PF‑08634404, alone or in combination regimens, in alignment with established effective RCC treatment paradigms. Previously presented in part at the 2026 AACR Annual Meeting.
T. Choueiri, Sumanta Pal, Thomas Powles et al.· The Oncologist· 0 citations
Abstract Background Despite improved outcomes with programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors (ICI) in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), most patients develop resistance. Preclinical data demonstrate that Janus kinase inhibition (JAKi) restores T cell cytokine production and proliferation, potentiating ICI activity, with ruxolitinib plus ICI demonstrating superior tumor control across multiple murine models. Ruxolitinib may also reprogram immunosuppressive myeloid populations within the tumor microenvironment. In an investigator-initiated trial (NCT03681561), 53% of patients with relapsed/refractory Hodgkin’s Lymphoma previously failing anti-PD-1 therapy responded to ruxolitinib plus nivolumab, including 6 complete responses. High response rates were also observed with JAKi plus anti-PD-1 in NSCLC (NCT03425006). We aim to investigate whether combining ruxolitinib with anti-PD-1 therapy can overcome resistance in solid tumors. Methods This prospective, open-label, single-arm phase 1b study evaluates ruxolitinib plus retifanlimab in patients with advanced clear cell RCC or NSCLC progressing on prior PD-1/PD-L1 therapy. Patients must have measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Key exclusions: prior JAKi, >1 prior line of PD-1/PD-L1 therapy, primary progression on prior ICI, or unresolved immune-related adverse event (>grade 1). A 3 + 3 dose escalation design evaluates ruxolitinib 15 mg and 20 mg twice daily with fixed retifanlimab 500mg intravenously (IV) every 4 weeks, followed by dose expansion. Treatment continues until progression, toxicity, or withdrawal. The primary objective is determining the recommended phase 2 dose (RP2D). Secondary objectives include objective response rate, duration of response, radiographic progression-free survival, overall survival, and safety. To further interrogate mechanisms of response and resistance, correlative studies evaluating tumor microenvironment, immune cell composition, and molecular profiling are ongoing. A Simon’s two-stage design is utilized for testing the null hypothesis (true response rate 10%) against an alternative of 30%, rejecting null if ≥ 6 responses occur in 25 participants (α = 0.05, power 80%). Assuming a dropout rate of 5%, we will target a minimum enrollment of 36 and maximum enrollment of 42 participants to ensure a maximum of 40 evaluable participants on the trial. The standard survival analysis will be conducted for the time-to-event endpoints. The study is activated at the University of California San Diego and is currently open to accrual. Clinical Trial Information: NCT07219576. Results Resistance to PD-1/PD-L1 blockade is a major unmet need in RCC and NSCLC, with few effective options after progression on frontline immunotherapy. PRISM tests a mechanistically rational combination, ruxolitinib to reverse chronic interferon-driven T cell dysfunction and immunosuppressive myeloid skewing, paired with retifanlimab to sustain antitumor T cell activity. Integrated correlative studies aim to identify biomarkers of response to guide patient selection. Our vision is to establish JAK inhibition as a tractable strategy for restoring checkpoint sensitivity across solid tumors, providing the foundation for a biomarker-driven randomized phase 2 trial in checkpoint-refractory disease. Conclusions NA23 Figure
Rana McKay, L.-J. Wei, Yu-Wei Chen et al.· The Oncologist· 0 citations
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