gartisertib (M4344) / EMD Serono, Vertex - LARVOL DELTA

Semi-mechanistic efficacy model for PARP + ATR inhibitors-application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs. (PubMed, Br J Cancer) - "By enabling simulation of in vivo tumour growth inhibition with PARP and ATR inhibitors for specific tumour types, the model provides a rational approach to support the optimisation of dosing regimens to stratified populations."

Journal • Breast Cancer • Oncology • Solid Tumor

Semi-mechanistic efficacy model for PARP + ATR inhibitors—application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs (Br J Cancer, Nature) - "The model successfully captured the monotherapy efficacies of rucaparib and talazoparib, as well as the combination efficacy with gartisertib. The model was evaluated against multiple tumour xenografts with diverse genetic backgrounds and was able to capture the observed heterogeneity of response profiles."

Preclinical • Breast Cancer

Semi-mechanistic efficacy model for PARP + ATR inhibitors—application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs (Br J Cancer, Nature) - "The model successfully captured the monotherapy efficacies of rucaparib and talazoparib, as well as the combination efficacy with gartisertib. The model was evaluated against multiple tumour xenografts with diverse genetic backgrounds and was able to capture the observed heterogeneity of response profiles."

Preclinical • Breast Cancer

Combined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer. (PubMed, Cancers (Basel)) - "The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted."

Journal • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Psychiatry • Solid Tumor • EGFR • KRAS

Overcoming Olaparib Resistance in BRCA-Mutated Triple-Negative Breast Cancer: Synergistic Potential of DNA Repair Pathway Inhibitors (SABCS 2024) - "Two PARP inhibitors (olaparib and talazoparib) are FDA-approved for patients with metastatic gBRCA mutated breast cancer...Based on target identification, we selected inhibitors of ATR (elimusertib, gartisertib), ATM (AZD1390), PLK4 (CFI-400945), CDK12 (SR-4835), PI3KCA (copanlisib), and AKT (capivasertib) for proliferation assays... Our preclinical study identified DNA repair pathways as potential targets to enhance the efficacy of olaparib in both parent and olaparib-refractory gBRCA mutated TNBC cell lines. Future in vivo studies, including patient-derived xenografts and additional mechanistic analyses to further understand dual DNA targeting synergy, are warranted to validate this therapeutic approach for TNBC with gBRCA mutation."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CDK12 • DRD • HER-2 • PIK3CG • PIK3R3 • PLK4

ATR inhibitors increase the anti-proliferative effects of standard treatment on patient-derived glioblastoma cells (EANO 2024) - "Background: Glioblastoma is treated with surgery to remove as much as the tumour as possible then radiation therapy (RT) and temozolomide (TMZ) to cause extensive DNA damage in any remaining tumour cells, triggering cell death by apoptosis. We have expanded our in vitro data showing that various ATR inhibitors (elimusertib, ceralasertib and previously gartisertib) are able to reduce the growth of glioblastoma cells in combination with RT and TMZ treatment. This provides further support for initiating a clinical trial of ATR inhibition in combination with standard treatment for patients with glioblastoma."

Clinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Chemo-phosphoproteomic profiling with ATR inhibitors berzosertib and gartisertib uncovers new biomarkers and DNA damage response regulators. (PubMed, Mol Cell Proteomics) - "We also show that SCAF1 deficiency partly rescues RAD51 loading in cells lacking the BRCA1 tumour suppressor. Taken together these data reveal potential new ATR biomarkers and new genome maintenance factors."

Biomarker • Journal • Oncology • Solid Tumor • BRCA1 • RAD51

The novel ATR inhibitor M1774 induces replication protein overexpression and broad synergy with DNA-targeted anticancer drugs. (PubMed, Mol Cancer Ther) - "As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib, but less potency than gartisertib and elimusertib in the small-cell lung cancer H146, H82, and DMS114 cell lines. Low dose of M1774 was found highly synergistic with a broad spectrum of clinical DDAs including TOP1 inhibitors (SN-38/irinotecan, topotecan, exatecan, and exatecan), the TOP2 inhibitor etoposide, cisplatin, the RNA polymerase II inhibitor lurbinectedin, and the PARP inhibitor talazoparib in various models including cancer cell lines, patient-derived organoids, and mouse xenograft models. Furthermore, we demonstrate that M1774 reverses chemoresistance to anticancer DDAs in cancer cells lacking SLFN11 expression, suggesting that SLFN11 can be utilized for patient selection in upcoming clinical trials."

Journal • Ataxia • Immunology • Lung Cancer • Movement Disorders • Oncology • Primary Immunodeficiency • Small Cell Lung Cancer • Solid Tumor • CCNB1 • CDC45 • CHEK1 • PLK1 • SLFN11 • TOP1

A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours. (PubMed, Br J Cancer) - P1 | "Gartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued."

Combination therapy • Journal • Metastases • P1 data • Ataxia • Hepatology • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor

ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines. (PubMed, Oncotarget) - "Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways. Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation."

Journal • Preclinical • Ataxia • Brain Cancer • CNS Tumor • Glioblastoma • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • MGMT

ATR inhibition as a novel radiosensitization strategy for glioblastoma (SNO 2023) - "Glioblastomas (GBM) are lethal brain tumors for which surgical resection followed by ionizing radiation (IR) with concurrent and adjuvant Temozolomide (TMZ) remains the mainstay of therapy...We treated a panel of GBM cell lines and normal human astrocytes with the ATR inhibitor VX-803 and/or IR and assessed for multiple endpoints including HR, DSB repair, and cell survival...Importantly, the drug does not significantly affect DSB repair in normal brain cells indicating that ATR inhibition might selectively block repair in GBM cells, thereby minimizing normal tissue toxicity. Our results indicate that regulation of HR by ATR is critical for optimal DSB repair, especially in rapidly-dividing GBM cells, and that ATR inhibition could be used to improve GBM radiotherapy in the clinic."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

[PREPRINT] ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines (bioRxiv) - "We showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment. MGMT promoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways."

Preclinical • Preprint • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Targeting non-oncogene addiction as new combined therapeutic strategy to overcome TKI-induced resistance in NSCLC (EACR 2023) - "In particular, we focused on ATM/ATR involved in DNA damage response (DDR); PKM2, PDK1, LDH-A and complex I of OXPHOS involved in energy metabolism and Bcl-2/Bcl-xL involved in antiapoptotic processes.Material and MethodsH1993, H1975 and A549 oncogene-driven NSCLC cells were treated with TKIs (crizotinib, osimertinib or erlotinib) and in parallel with a combination of two of selected NOA inhibitors (DCA, benserazide, oxamate, IACS-10759, KU55933, M4344 and ABT-263). Finally, PDKs inhibition with DCA caused a significant dose-dependent decrease of glucose consumption and increase of OXPHOS subunits.ConclusionOur preliminary data suggest that targeting these proteins may destabilize tumor environment thus coupling metabolic phenotype and DDR to drug resistance. The major translational relevance of this study is to exploit these new targets for innovative and improved therapeutic strategies in comparison to TKI therapies in NSCLC patients."

IO biomarker • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Psychiatry • Solid Tumor • BCL2 • BCL2L1 • CCND1 • HIF1A • LDHA • LMNA • MYC • PKM • TP53

Trial of M4344 and Niraparib in Patients With Poly (ADP-ribose) Polymerase (PARP) Resistant Recurrent Ovarian Cancer (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: University of Alabama at Birmingham | N=40 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

Molecular pharmacology and broad synergy of the novel ATR inhibitor M1774 with DNA damaging anticancer agents (AACR 2023) - "As a single agent, we found that M1774 suppresses cancer cell viability at nanomolar concentrations with a potency higher than ceralasertib and berzosertib, but lower than gartisertib (M4344) and elimusertib in the small cell lung cancer (SCLC) cell lines H146, H82, and DMS114...Low doses of M1774 significantly synergized with the clinical TOP1 inhibitor SN-38, the TOP2 inhibitor etoposide, cisplatin, and the PARP inhibitor talazoparib in SCLC cell lines...The synergistic efficacy between M1774 and DNA-damaging agents was confirmed in SCLC patient-derived organoids, colon cancer patient-derived organoids, and H82 SCLC xenografts. Together, these results provide insights into the molecular mechanism and potential combination strategies for M1774 in cancer therapy."

Late-breaking abstract • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • CCNB1 • CDC45 • CHEK1 • PLK1 • RPA1 • SLFN11 • TOP1

ATR inhibition as a novel radiosensitization strategy for glioblastoma (ESTRO 2023) - "Purpose or Objective Glioblastomas (GBM) are lethal brain tumors for which surgical resection followed by treatment with ionizing radiation (IR) and concurrent administration of Temozolomide (TMZ) is the mainstay of therapy...We therefore hypothesized that ATR inhibition would block DSB repair in rapidly-dividing GBM cells that are HR dependent but not in non-dividing normal brain cells that are dependent upon NHEJ for repair.  Material and Methods A panel of GBM cell lines and normal human astrocytes were treated with VX-803 and/or IR and assessed for multiple endpoints including HR, DSB repair, and cell survival...In vivo, we find that the drug can cross the blood-brain barrier and, in conjunction with IR, block DNA repair in intracranial tumors, attenuate tumor growth, and consequently extend survival of tumor-bearing mice. Importantly, the drug does not significantly affect DSB repair in normal brain cells indicating that ATR inhibition might selectively block..."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Selective inhibition of ATM-dependent double-strand break repair and checkpoint control synergistically enhances the efficacy of ATR inhibitors. (PubMed, Mol Cancer Ther) - "In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1 phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell cycle checkpoints and DSB repair, lowered the p53 protective barrier and extended the life of ATR inhibitor induced DSBs...ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Further, a combination study in 26 patient-derived xenograft models of triple negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared to single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy."

Journal • Ataxia • Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer

Development and validation of a quantitative systems pharmacology model for prediction of preclinical efficacy of PARP inhibitors rucaparib and talazoparib combined with the ATR inhibitor gartisertib (M4344) (AACR 2023) - "This newly developed QSP model provides a framework that can be applied to optimize the dosing regimens of PARP and ATR inhibitor combinations and help with clinical dosing strategy."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA

Trial of M4344 and Niraparib in Patients With Poly (ADP-ribose) Polymerase (PARP) Resistant Recurrent Ovarian Cancer (clinicaltrials.gov) - P1 | N=40 | Not yet recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: Dec 2027 ➔ May 2027 | Trial primary completion date: Dec 2023 ➔ May 2024

Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma. (PubMed, JCI Insight) - "M4344 synergises with chemotherapeutic drugs including cisplatin and carboplatin and the PARP inhibitor olaparib in mouse and human ccRCC cells. Weekly M4344 plus cisplatin treatment showed in vivo therapeutic synergy in ccRCC xenografts and was efficacious in an autochthonous mouse ccRCC model. These studies identify ATR inhibition as a potential novel therapeutic option for ccRCC."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Immune Modulation • Inflammation • Oncology • Renal Cell Carcinoma • Solid Tumor • Urology

Trial of M4344 and Niraparib in Patients With Poly (ADP-ribose) Polymerase (PARP) Resistant Recurrent Ovarian Cancer (clinicaltrials.gov) - P1; N=40; Not yet recruiting; Sponsor: University of Alabama at Birmingham; Trial primary completion date: Dec 2022 ➔ Dec 2023

Trial primary completion date • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

ATR Inhibitor Combinations Begin to Tackle DNA Damage Repair in Solid Tumors (Targeted Oncology) - "Haider S. Mahdi, MD...commented in an interview with Targeted Therapies in Oncology™ on the current state of ATR inhibitor therapy: 'There are trials looking at patients with solid tumors with deficiency in the DDR pathway; most of them are early-phase trials, and most are cancer specific.'...The included patients were all heavily pre-treated with a median of 4 prior therapies (range, 0-10) and patients with highgrade serous ovarian cancer were PARP inhibitor–resistant but still saw clinical benefit. 'Low response rate could be due to the fact we didn’t limit the previous number of lines of therapy,' commented Mahdi."

Interview

First in Human Study of M4344 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=98; Completed; Sponsor: EMD Serono Research & Development Institute, Inc.; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Oncology • Solid Tumor • ARID1A • ATRX

Study of M4344 in Combination With Niraparib (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: EMD Serono Research & Development Institute, Inc.; N=164 ➔ 0; Not yet recruiting ➔ Withdrawn

Combination therapy • Enrollment change • Trial withdrawal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2 • HRD

[VIRTUAL] Novel and highly potent ATR inhibitor M4344 kills cancer cells with replication stress and enhances the chemotherapeutic activity of widely used DNA damaging agents (AACR 2021) - "Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models.Experimental design: The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib...It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models. M4344 is a promising and highly potent ATR inhibitor. M4344 is a promising and highly potent ATR inhibitor. It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin and talazoparib. RepStress and NE gene expression signatures can be exploited as predictive markers for M4344."

Oncology