REC-4881 / Takeda, Recursion Pharma - LARVOL DELTA

STAG2 expression imparts distinct therapeutic vulnerabilities in muscle-invasive bladder cancer cells. (PubMed, Oncogenesis) - "We identified 100 total drug hits and found that STAG2 KO sensitized cells to treatment with PLK1 inhibitor rigosertib, whereas STAG2 KO protected cells from treatment with MEK inhibitor TAK-733 and PI3K inhibitor PI-103. Finally, synergy experiments revealed that berzosertib exhibits significant synergistic cytotoxicity in combination with cisplatin against MIBC cells. Altogether, our study presents evidence that berzosertib, PI-103, and the combination of berzosertib with cisplatin may be novel opportunities to investigate as precision medicine approaches for MIBC patients based on STAG2 tumor expression."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • STAG2

Analysis of nitrogen metabolism-related gene expression in hepatocellular carcinoma to establish relevant indicators for prediction of prognosis and guidance of immunotherapy. (PubMed, Comput Methods Biomech Biomed Engin) - "This work created a 12-gene signature based on NM, preliminary investigated immune infiltration in two risk categories, and discovered some possible anti-tumor medications. To sum up, our study findings offer fresh perspectives on the roles played by NM-associated genes in HCC development, prognosis, immunological response, and medication screening."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • SPHK1 • YARS1

Combinatorial Targeting of Common Docking and ATP Binding Sites on Mps1 MAPK for Management of Pathogenic Fungi. (PubMed, J Agric Food Chem) - "In vivo assays demonstrated that TAK-733 exhibits combinational effects with ATP-competitive inhibitors PLX-4720 and A378-0. Collectively, we present TAK-733 as having a new mechanism of action suitable for combinational application with ATP-competitive inhibitors in the management of pathogenic fungi."

Journal • MAP2K1

A Study of REC-4881 in Participants with Cancers Which Have an AXIN1 or APC Mutation (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Recursion Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Colorectal Cancer • Oncology • Solid Tumor • APC • AXIN1 • RAS

Recursion Provides Business Updates and Reports Third Quarter 2024 Financial Results (GlobeNewswire) - "Summary of Business Highlights:...(i) Neurofibromatosis Type 2 (NF2) (REC-2282): Our adaptive Phase 2/3 POPLAR clinical trial is an open label, two part study of REC-2282 in participants with progressive NF2-mutated meningiomas....Enrollment of adult patients in Part 1 of the study is complete (n=24). We expect to share an update in Q4 2024....(ii) APC or AXIN1 Mutant Cancers (REC-4881): Our Phase 2 LILAC clinical trial is an open label, multicenter study of REC-4881 in participants with unresectable, locally advanced or metastatic cancer with AXIN1 or APC mutations. We expect to share Phase 2 safety and preliminary efficacy data in H1 2025."

Enrollment status • P2 data • P2/3 data • Neurofibromatosis • Solid Tumor

Recursion Provides Business Updates and Reports Fourth Quarter and Fiscal Year 2023 Financial Results (GlobeNewswire) - "AXIN1 or APC Mutant Cancers (REC-4881): Our Phase 2 LILAC clinical trial is an open label, multicenter study of REC-4881 in participants with unresectable, locally advanced or metastatic cancer with AXIN1 or APC mutations. This study was initiated at the end of 2023, with FPI anticipated in Q1 2024. We expect to share Phase 2 safety and preliminary efficacy data in H1 2025."

P2 data • Trial status • Solid Tumor

A Study of REC-4881 in Participants With Cancers Which Have an AXIN1 or APC Mutation (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Recursion Pharmaceuticals Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • APC • AXIN1 • RAS

A Study of REC-4881 in Participants With Cancers Which Have an AXIN1 or APC Mutation (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Recursion Pharmaceuticals Inc. | Initiation date: Oct 2023 ➔ Jan 2024

Metastases • Trial initiation date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • APC • AXIN1 • RAS

TUPELO: Evaluate REC-4881 in Patients With FAP (clinicaltrials.gov) - P1/2 | N=73 | Recruiting | Sponsor: Recursion Pharmaceuticals Inc. | Phase classification: P2 ➔ P1/2 | N=37 ➔ 73

Enrollment change • Phase classification • Genetic Disorders • APC

Integrating bulk and single-cell RNA sequencing data reveals epithelial-mesenchymal transition molecular subtype and signature to predict prognosis, immunotherapy efficacy, and drug candidates in low-grade gliomas. (PubMed, Front Pharmacol) - "In addition, several promising drugs, including birinapant, fluvastatin, clofarabine, dasatinib, tanespimycin, TAK-733, GDC-0152, AZD8330, trametinib and ingenol-mebutate had great potential to the treatment of high risk patients. Our research revealed non-negligible role of EMT in the TME diversity and complexity of LGG. A prognostic signature may contribute to the personalized treatment and prognostic determination."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • SLC39A1

Multi-omics analysis reveals CLIC1 as a therapeutic vulnerability of gliomas. (PubMed, Front Pharmacol) - "High CLIC1 expression samples were more sensitive to camptothecin, cisplatin, doxorubicin, erlotinib, paclitaxel, rapamycin, clofarabine, tanespimycin, methotrexate, everolimus, TAK-733, trametinib and AZD8330. Single-cell analysis unveiled that CLIC1 was expressed ubiquitously in tumor cells and tumor microenvironment. Overall, CLIC1 was a promising treatment vulnerability in glioma."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CLIC1

Recursion Provides Business Updates and Reports Third Quarter 2023 Financial Results (GlobeNewswire) - "Recursion...today reported business updates and financial results for its third quarter ending September 30, 2023....Our Phase 2 LILAC clinical trial is a biomarker enriched two part study of REC-4881 in participants with unresectable, locally advanced or metastatic cancer with AXIN1 or APC mutations. The study will initiate in late Q4 2023 or early Q1 2024 and will explore the safety and efficacy of REC-4881 across three dose levels in 30-40 participants."

New P2 trial • Oncology • Solid Tumor

TUPELO: Evaluate REC-4881 in Patients With FAP (clinicaltrials.gov) - P2 | N=37 | Recruiting | Sponsor: Recursion Pharmaceuticals Inc. | N=94 ➔ 37

Enrollment change • Genetic Disorders • APC

A Study of REC-4881 in Participants With Cancers Which Have an AXIN1 or APC Mutation (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Recursion Pharmaceuticals Inc.

Metastases • New P2 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • APC • AXIN1 • RAS

Recursion Provides Business Updates and Reports Second Quarter 2023 Financial Results (GlobeNewswire) - "AXIN1 or APC Mutant Cancers (REC-4881): We will evaluate REC-4881 in a Phase 2 biomarker enriched study in patients with unresectable, locally advanced or metastatic cancer with AXIN1 or APC mutations. The IND was accepted by the FDA and we expect to initiate this Phase 2 study in Q4 2023."

IND • New P2 trial • Oncology • Solid Tumor

TUPELO: Efficacy and Safety of REC-4881 in Participants With Familial Adenomatous Polyposis (FAP) (clinicaltrials.gov) - P2 | N=94 | Recruiting | Sponsor: Recursion Pharmaceuticals Inc. | Trial completion date: Mar 2026 ➔ Jul 2026 | Trial primary completion date: Mar 2026 ➔ Jul 2026

Trial completion date • Trial primary completion date • Genetic Disorders • APC

Recursion Provides Business Updates and Reports First Quarter 2023 Financial Results (GlobeNewswire) - "Neurofibromatosis Type 2 (NF2) (REC-2282): Our Phase 2/3 POPLAR clinical trial is a parallel group, two stage, randomized, multicenter study of this drug candidate in approximately 90 participants with progressive NF2-mutated meningiomas. Enrollment is ongoing and we expect to share a Phase 2 interim safety analysis in 2024....AXIN1 or APC Mutant Cancers (REC-4881)…We expect to initiate a Phase 2 biomarker enriched study across select AXIN1 or APC mutant solid tumors in early 2024."

New P2 trial • P2 data • Neurofibromatosis • Oncology • Solid Tumor

TUPELO: Efficacy and Safety of REC-4881 in Participants With Familial Adenomatous Polyposis (FAP) (clinicaltrials.gov) - P2 | N=94 | Recruiting | Sponsor: Recursion Pharmaceuticals Inc. | N=171 ➔ 94

Enrollment change • Genetic Disorders • APC

TUPELO: Efficacy and Safety of REC-4881 in Participants With Familial Adenomatous Polyposis (FAP) (clinicaltrials.gov) - P2 | N=171 | Recruiting | Sponsor: Recursion Pharmaceuticals Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • APC

TUPELO: Efficacy and Safety of REC-4881 in Participants With Familial Adenomatous Polyposis (FAP) (clinicaltrials.gov) - P2 | N=171 | Not yet recruiting | Sponsor: Recursion Pharmaceuticals Inc.

New P2 trial • Genetic Disorders • APC

A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer. (PubMed, Biochem Pharmacol) - "On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. In a group of 219 patients with metastasized ER+ breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome."

Journal • Breast Cancer • Hematological Malignancies • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ALK • IGF1R • MAP2K1

MEK 1/2 inhibitors in the treatment of gynecologic malignancies (Gynecol Oncol) - “This paper reviews the translational evidence in favor of MEK inhibitors in cancer, their role in gynecologic malignancies, and details regarding the status of the fourteen MEK inhibitors currently being clinically tested: trametinib, selumetinib, pimasertib, refametinib, PD-0325901, MEK162, TAK733, RO5126766, WX-554, RO4987655, cobimetinib, AZD8330, MSC2015103B, and ARRY-300.” 

Review • Oncology

Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres. (PubMed, Cells) - "To mimic a stem-like phenotype, glioblastoma-derived spheres were used and treated with a combination of HDACi (MS-275) and MEKi (TAK-733 or trametinib) with 4 Gy irradiation. Finally, we showed that the combined treatment with radiation was more effective at reducing the GSLC markers compared to the standard treatment of temozolomide and radiation. These results suggest that combining HDAC and MEK inhibition with radiation may offer a new strategy to improve the treatment of glioblastoma."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD44 • NES • SOX2

Combined CDK inhibition overcomes MEK inhibitor resistance in plexiform neurofibroma of neurofibromatosis type I. (PubMed, J Invest Dermatol) - "Coadministration of dinaciclib and TAK-733 significantly reduced cell viability, inhibited sphere formation and colony formation. Therefore, the combination of MEKi and CDKi may be promising for treating inoperable PNFs, especially when drug resistance exists. Our findings provide evidence for future clinical trials with MEKi-resistant PNF patients."

Journal • Fibrosis • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • BIRC5 • CDK1 • NF1

MEK1 Inhibitor Combined with Irradiation Reduces Migration of Breast Cancer Cells Including miR-221 and ZEB1 EMT Marker Expression. (PubMed, Cancers (Basel)) - "This leads to the assumption that radiation alone is not reducing migration capacity of miR-221-overexpressing cells and that additional factors play an important role in this context. The miR-221/ZEB1 activity is efficiently targeted upon MEK1 inhibitor (TAK-733) treatment and when combined with irradiation treatment, significant reduction in migration of breast cancer cells was shown."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer