Biology subjects

Buchsbaum, D. J.

Publications and source records attributed to Buchsbaum, D. J..

6 recordsLinked to original sources

bioRxiv2026

ADT-030, a novel PDE10 inhibitor, demonstrates potent antitumor activity in pancreatic ductal adenocarcinoma

Phosphodiesterase 10 (PDE10) has been noted to be highly expressed in multiple types of cancer and is crucial for the growth and maintenance of cancer cells found in colon, lung, and ovarian cancers. Here, we studied a novel orally bioavailable PDE10 inhibitor, ADT-030, and found that it potently inhibits the proliferation and clonogenicity of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cells at levels that block recombinant PDE10. ADT-030 also inhibited PDAC cell motility and triggered G2/M cell cycle halt and programmed cell death. These impacts were facilitated by raised cAMP/cGMP levels, activation of PKA/PKG, reduced {beta}-catenin and RAS signaling. Notably, ADT-030 diminished the proliferation of PDAC cells with KRASG12D and KRASG12C mutations that were resistant to both allele-specific and pan-RAS inhibitors. When administered orally, ADT-030 markedly decreased tumor growth, lowered the metastasis to the lungs and liver, and enhanced survival rates without causing systemic toxicity in both syngeneic and patient-derived xenograft (PDX) models of PDAC. ADT-030 also increased chemotherapy response in orthotopic PDAC models. Immune phenotyping and single-cell RNA sequencing revealed remodeling of the tumor microenvironment by ADT-030 with a more favorable anti-tumor immune profile. The findings suggest that ADT-030 holds promise as a potential drug development candidate for treating KRAS-mutant PDAC by simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects.

cancer biology↗

bioRxiv2025

Potency and selectivity of a novel pan-RAS inhibitor in 3D bioprinted organoid tumor models

BackgroundColorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving [~]40% of cases. Efficacy of recently approved, mutant-specific KRAS inhibitors is limited by intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as ADT-007, offer broader therapeutic potential by targeting multiple RAS isoforms. Here, we evaluate ADT-007 in 3D bioprinted organoid tumors (BOTs) generated from KRAS-mutant and RAS wild-type (WT) CRC cell lines. MethodsPotency and selectivity of ADT-007 were compared to bortezomib, a proteasome inhibitor, and YM155, a survivin inhibitor, using high-content imaging and ATP-based luminescence assays. Mechanistic studies assessed impact on RAS activation and downstream signaling. ResultsADT-007 exhibited high potency and selectivity in KRAS-mutant BOTs, reducing tumor burdens >30% at nanomolar concentrations, and demonstrated superior selectivity over bortezomib and YM155 with minimal cytotoxicity in RAS-WT BOTs. Mechanistic analysis confirmed ADT-007 inhibited RAS activation and downstream signaling, leading to selective apoptosis induction in KRAS-mutant CRC cells. ConclusionsThe selective potency and specificity of ADT-007 warrants further investigation of pan-RAS inhibitors for treating RAS-driven cancers. This study also underscores the translational utility of 3D BOT models for preclinical drug response assessment. Further validation in patient-derived BOTs is necessary to evaluate potential of ADT-007 in clinical settings.

bioengineering↗

bioRxiv2024

ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma

Here, we evaluated in vivo antitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations. ADT-1004 treatment increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRASG12C inhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RASWT PDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development. SignificanceADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

cancer biology↗

bioRxiv2023

Novel Pan-RAS Inhibitor ADT-007 Induces Tumor Regression in Mouse Models of GI Cancer

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RASWT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RASWT and normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers. SIGNIFICANCEADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.

cancer biology↗

bioRxiv2022

ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds 2,6-linked sialic acids to N-glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft models with human PDAC cells. Additionally, we developed a genetically-engineered mouse (GEM) with transgenic expression of ST6GAL1 in the pancreas, and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D have greatly accelerated PDAC progression and mortality compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1s role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We confirmed that ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a novel glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.

cancer biology↗

bioRxiv2019

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation.

Breast cancers can be divided into subtypes with different prognoses and treatment responses based on global gene expression differences. Luminal breast cancer gene expression and proliferation are driven by the transcription factors Estrogen Receptor (ER), FOXA1 and GATA3. Targeting ER is the most effective therapy for treating luminal breast cancer because ER is the master regulator of the luminal gene expression program. In contrast, it is unclear which transcription factors are responsible for driving the gene expression signature that defines basal-like triple negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype of the disease. This study utilized integrated analysis of DNA methylation, chromatin accessibility, transcription factor binding, and gene expression in large collections of breast cancer cell lines and patient tumors to identify transcription factors responsible for the basal-like gene expression program. The results of this study indicate that glucocorticoid receptor (GR) and signal transducer and activator of transcription 3 (STAT3) bind to the same genomic regulatory regions that are specifically open and unmethylated in basal-like breast cancer. These transcription factors cooperate to regulate expression of hundreds of genes in the basal-like gene expression signature and these downstream genes are associated with poor prognosis in patients. Furthermore, combination treatment with small molecule drugs that inhibit both transcription factors leads to synergistic decreases in cell proliferation in cell lines and patient-derived organoid models. This study demonstrates that GR and STAT3 cooperate to regulate the basal-like breast cancer gene expression program and provides the basis for improved therapy for basal-like triple negative breast cancer through rational combination of STAT3 and GR inhibitors.

cancer biology↗