ADT-030 / ADT Pharma - LARVOL DELTA

Targeting phosphodiesterase 10A disrupts MAPK signaling pathways in the tumor microenvironment to unleash antitumor immunity. (PubMed, bioRxiv) - "Mechanistically, ADT-030 disrupts multiple components of the mitogen-activated protein kinase (MAPK) signaling network in both tumor cells and MDSCs, leading to induction of apoptosis in these populations. These findings highlight the multi-faceted impact of PDE10A inhibition as a therapeutic strategy that not only disrupts tumor-intrinsic oncogenic signaling to inhibit tumor progression but also reshapes the tumor immune microenvironment to unleash antitumor immunity."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • BATF3 • CD8

Targeting phosphodiesterase 10A by ADT-030 normalizes the tumor immune microenvironment by inhibiting RAS-MAPK signaling in both cancer cells and myeloid-derived suppressor cells (AACR 2026) - "Comprehensive immune profiling in the 4T1 triple-negative breast cancer model, both in orthotopic and metastatic settings, revealed that ADT-030 selectively reduces tumor-associated neutrophils while restoring the presence and function of CD8+ T cells. These findings highlight PDE10A inhibition as a multi-faceted strategy that not only disrupts tumor-intrinsic oncogenic signaling but also reshapes the tumor immune microenvironment to unleash antitumor immunity."

Myeloid-derived suppressor cells • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8

ADT-007: A mechanistically distinct Pan-RAS inhibitor with capacity to escape acquired resistance common to other RAS inhibitors (AACR 2026) - "Furthermore, RAS mutant colon and pancreatic cancer cells did not develop resistance to ADT-007 under chronic exposure, in contrast to sotorasib, BI-2865, and RMC-6236, which readily produced cultures that were essentially unresponsive to the inhibitor they were exposed to. Moreover, the resistant cell lines exhibited cross-resistance to mechanistically distinct classes of RAS inhibitors, including pan-KRAS, pan-RAS, and allele-specific KRAS inhibitors, but not to ADT-007 or a second-generation inhibitor, ADT-030...Consistent with resistance experiments, ADT-1004 displayed superior efficacy than sotorasib or adagrasib in a xenograft model using a resistant MIA-PaCa-2. These findings support further development of ADT-1004 that holds promise for broad and durable efficacy against RAS-driven cancers."

Preclinical • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Robust and durable antitumor activity of a novel PDE10 inhibitor, ADT-030, that enhances the efficacy of chemotherapy and immunotherapy by blocking RAS and β-catenin signaling and overcoming resistance to RAS-selective inhibitors (AACR 2026) - "ADT-030 also enhanced the antitumor activity of chemotherapy (paclitaxel) and immune checkpoint inhibitors in mouse models of lung, colon, and breast cancer. Deep immunophenotyping studies revealed a significant impact of ADT-030 treatment on the tumor immune microenvironment, characterized by the selective induction of apoptosis in myeloid-derived suppressor cells (MDSC), while increasing tumor infiltration by CD8+ T cells and natural killer cells. These results show that ADT-030 has potential advantages over direct-acting RAS inhibitors, supporting clinical trials of ADT-030 as a monotherapy or in combination with chemotherapy or immunotherapy for a broad range of RAS-driven cancers."

Clinical • IO biomarker • Breast Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • KRAS

ADT-030, a novel PDE10 inhibitor, demonstrates potent antitumor activity in pancreatic ductal adenocarcinoma. (PubMed, bioRxiv) - "Immune phenotyping and single-cell RNA sequencing revealed remodeling of the tumor microenvironment by ADT-030 with a more favorable immune suppressive profile to activate anti-tumor immunity. These results show that ADT-030 is a promising drug development candidate for the treatment of KRAS-mutant PDAC capable of simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

A novel PDE10 inhibitor that blocks RAS and β-catenin signaling and enhances tumor immunogenicity with robust activity to inhibit tumor growth and metastasis (AACR-NCI-EORTC 2025) - "Moreover, ADT-030 augmented the efficacy of anti-PD1 antibody therapy in mice bearing CT26 tumors harboring the KRAS G12D mutation. Together, these results support IND-enabling studies of ADT-030 as monotherapy or combined with immunotherapy for a broad range of cancers."

IO biomarker • Breast Cancer • Colon Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • KRAS

Targeting phosphodiesterase 10 unleashes antitumor immunity by inhibiting the RAS-MAPK signaling in cancer cells and myeloid-derived suppressor cells (IMMUNOLOGY 2025) - "Moreover, ADT030-induced immunogenic cell death in cancer cells promoted dendritic cell antigen uptake and maturation. Altogether, our study provides insight into the mechanism of action of ADT-030 and underscores the potential of ADT-030 as a monotherapy or in combination with immunotherapies for treating cancers with mutant or activated RAS.Keywords: Animals Rodent; Cells Dendritic Cells Neutrophils T Cells; Molecules Protein Kinases/Phosphatases"

IO biomarker • Myeloid-derived suppressor cells • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD8

A novel dual inhibitor of RAS and β-catenin signaling with advantages over mutant-specific KRAS inhibitors to escape resistance has robust antitumor efficacy and activates antitumor immunity (AACR 2025) - "Finally, deep immunophenotyping studies revealed a significant impact of ADT-030 treatment on the tumor immune microenvironment characterized by selective induction of apoptosis in myeloid-derived suppressor cells (MDSC) while increasing tumor infiltration of CD8+ T cells and natural killer cells. Together, these results support IND-enabling studies of ADT-030 as a monotherapy or in combination with immunotherapy for a broad range of KRAS-driven/dependent cancers."

Clinical • IO biomarker • Breast Cancer • Colon Cancer • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BIRC5 • CD8 • KRAS

A novel 1st-in-class RAS/β-catenin inhibitor concurrently targets cancer cells and MDSC to reverse the immunosuppressive tumor microenvironment: antitumor activity in mouse models of breast and other cancers (SABCS 2024) - "Furthermore, ADT-030 treatment of cancer cells led to immunogenic cell death and enhanced dendritic cell activation. These results support further development of ADT-030, a novel PDE10 inhibitor capable of suppressing oncogenic RAS and β-catenin signaling, as a monotherapy or combined with immunotherapy or standard-of-care drugs for treating breast or other cancers with activated RAS and β-catenin signaling."

IO biomarker • Myeloid-derived suppressor cells • Preclinical • Tumor microenvironment • Breast Cancer • Oncology • CD8 • CTNNB1

A novel PDE10 inhibitor targets cancer cells and MDSC to reverse the immunosuppressive tumor microenvironment: antitumor activity in multiple tumor types (EORTC-NCI-AACR 2024) - "Furthermore, ADT-030 treatment of cancer cells led to immunogenic cell death and enhanced dendritic cell activation. These results support further development of ADT-030, a novel PDE10 inhibitor capable of suppressing oncogenic RAS and β-catenin signaling, as a monotherapy or combined with immunotherapy for RAS and β-catenin driven cancers."

Biomarker • IO biomarker • Late-breaking abstract • Myeloid-derived suppressor cells • Tumor microenvironment • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD8

Survival benefit and tumor regression with a dual RAS/β-catenin inhibitor, ADT-030, in murine models of pancreatic and lung cancer (EORTC-NCI-AACR 2024) - "These results show robust and durable antitumor activity of ADT-030, a novel pan-RAS/β-catenin inhibitor, in highly aggressive and clinically relevant models of RAS-driven cancers. Thus, ADT-030 represents a development candidate for combating the challenges posed by complex mutations in PDAC, NSCLC, and other RAS-driven cancers and support its clinical evaluation as a valuable therapeutic alternative to mutant-specific KRAS or other pan-RAS inhibitors in development."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CTNNB1 • KRAS

A novel pan-RAS/β-catenin inhibitor, ADT-030, produces tumor regression in PDX models of pancreatic cancer (AACRPanCa 2024) - "ADT-030, novel dual pan-RAS/β-catenin inhibitor, showed strong and durable antitumor activity in clinically relevant and aggressive murine models of PDAC and lung cancer. ADT-030 is a promising development candidate for treatment of PDAC and other RAS-driven cancers, particularly given the complex KRAS mutation landscape of many cancers."

Gastrointestinal Cancer • Hepatology • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ANXA5 • CTNNB1 • KRAS

A Novel RAS/β-Catenin Inhibitor, ADT-030, Induces Tumor Regression and Inhibits Metastasis with "Cures" in Multiple Mouse Cancer Models (DOT 2024) - No abstract available

Preclinical • Oncology • CTNNB1

Evaluation of a novel Pan-RAS/β-Catenin inhibitor, ADT-030, for treatment of pancreatic cancer. (ASCO 2024) - "These compelling results position ADT-030 as a novel dual pan-RAS/β-catenin inhibitor for combating the challenges posed by complex mutations in PDAC and other RAS driven cancers and support its clinical evaluation as a valuable therapeutic alternative to mutant-specific KRAS inhibitors."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ANXA5 • CTNNB1 • KRAS

ADT-030 is a novel dual-acting RAS/β-catenin inhibitor that potentiates antitumor immunity (AACR 2024) - "Furthermore, the ability of ADT-030 to augment the antitumor activity of immune checkpoint blockade therapy underlines its potential as a desirable immune-potentiating agent to improve the outcome of cancer immunotherapy. ADT-030 represents a development candidate ready for IND-enabling safety assessment."

IO biomarker • Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD8 • CTNNB1 • KRAS

ADT-030, a novel dual-acting RAS and β-catenin inhibitor with robust antitumor activity (AACR 2023) - "These results support further development of ADT-030, a novel inhibitor of RAS and β-catenin signaling for the treatment of lung cancer and other RAS driven cancers, including those with co-occurring mutations in the Wnt/β-catenin pathway."

Lung Cancer • Oncology • Solid Tumor • CTNNB1 • EGF • LINC00473

A novel dual-acting RAS/β-catenin inhibitor activates antitumor immunity to potentiate cancer immunotherapy (AACR 2023) - "Bulk and single-cell RNAseq is being conducted to determine the impact of ADT-030 on the cell compositions and transcriptomic changes in the TME. Altogether, our study provides insight into the mechanism of action of ADT-030 and underscores the potential of ADT-030 as a monotherapy or in combination with immunotherapies for RAS and Wnt/β-catenin driven cancers."

Breast Cancer • Oncology • Solid Tumor • CD8