AOH1996 / RLL, City of Hope - LARVOL DELTA

Assessment of Methods in AOH1996 Studies for Pancreatic Ductal Adenocarcinoma Therapy. (PubMed, Gastroenterology) - No abstract available

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

The PCNA inhibitor AOH1996 suppresses cancer stemness and enhances anti-PD1 immunotherapy in squamous cell carcinoma. (PubMed, Stem Cell Res Ther) - "Taken together, our results demonstrated that AOH1996 suppressed tumor growth, eliminated cancer stem cells (CSCs), and synergistically enhanced the efficacy of anti-PD1 immunotherapy in HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • PCNA • TBK1

AOH1996 for the Treatment of Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=92 | Recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Jan 2026 ➔ Sep 2029 | Trial primary completion date: Jan 2026 ➔ Sep 2029

First-in-human • Trial completion date • Trial primary completion date • Leiomyosarcoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Osteosarcoma • Ovarian Cancer • Pancreatic Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor • Synovial Sarcoma

A Phase 1 Study of AOH1996 in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Aug 2027 ➔ Jan 2027 | Trial primary completion date: Aug 2027 ➔ Jan 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Phase 1 Study of AOH1996 in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: City of Hope Medical Center | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Phase 1 Study of AOH1996 in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: City of Hope Medical Center | N=30 ➔ 12 | Trial completion date: Jan 2027 ➔ Aug 2027 | Trial primary completion date: Jan 2027 ➔ Aug 2027

Enrollment change • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Proliferating cell nuclear antigen as a new therapeutic target in multiple myeloma (AACR 2025) - "Increased expression of PCNA has been shown to be associated with an aggressive MM phenotype, making it an attractive therapeutic target. We tested the anti-tumor activity of the novel small molecule PCNA inhibitor AOH-1996 (alone and in combination with either bortezomib or venetoclax) against MM cell lines (MM1.S, SKMM2, RPMI-8226). These findings clearly suggest that PCNA is a potential therapeutic target in MM. We have demonstrated for the first time that the PCNA inhibitor AOH-1996 shows potent anti-myeloma activity through its effects on several key tumor-associated genes and miRNAs. AOH-1996 is currently being evaluated in a Phase I trial."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2 • CCL3 • CDK4 • CRBN • IL6 • MIR142 • MIR21 • MIR222 • PCNA • VIM

A novel PCNA inhibitor AOH1996 demonstrates pre-clinical efficacy in pancreatic ductal adenocarcinoma models (AACR 2025) - "We found that KRAS G12D inhibitor (MRTX1133) in combination with AOH1996 enhanced cytotoxicity in several PDAC cell lines at lower MRTX1133 concentrations, potentially reducing toxic side effects. We also observed enhanced efficacy of the chemotherapeutic agent oxaliplatin, which is a platinum compound in the FOLFIRINOX regimen, in combination with AOH1996. Collectively, our results show that AOH1996 is a promising agent for PDAC treatment which potentiates chemotherapy, and targeted KRAS G12D inhibitors. In vivo xenograft studies combining AOH1996 and KRAS inhibitors are ongoing."

Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PCNA

Advancing AOH1996: Enhanced anticancer activity of next-generation small molecule PCNA inhibitors (AACR 2025) - "Among these, AOH-3M5Me-6F and AOH-3M5Me-6CN emerged as the lead analogues, demonstrating up to nine- and seven-fold improved potency and 38% and 68% higher liver microsome stability, respectively. These findings position these analogues for further development as selective PCNA-targeting cancer therapies."

Oncology • PCNA

Targeting transcription-replication conflict for selective chemotherapy in glioblastoma (AACR 2025) - "The current standard of care for glioblastoma (GBM) is surgical intervention followed by a combination of temozolomide (TMZ) and radiation therapy. GBM cancer cells are, therefore, less likely to develop resistance to AOH1996 through mutagenesis in PCNA. If combined with the existing chemotherapeutic regime and inhibitors of DNA repair pathways, AOH1996 may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability to deliver a durable response in GBM."

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

AOH1996: A multi-faceted inhibitor of metastasis via PCNA and tumor microenvironment targeting (AACR 2025) - P1 | "Together, these findings establish AOH1996 as a multi-faceted therapeutic with significant anti-metastatic potential. By targeting both PCNA-dependent processes and the tumor microenvironment, AOH1996 could provide a unique approach for combating metastatic cancers."

Biomarker • Tumor microenvironment • Oncology • Osteosarcoma • Pancreatic Cancer • Sarcoma • Solid Tumor • MYC • PCNA

PCNA and histone deacetylase targeted inhibitors in cutaneous T-cell lymphoma (AACR 2025) - "Inspired by phosphoproteomic analyses of AOH1996-treated cells, we investigated its potential in combination therapy with the histone deacetylase inhibitors (HDACi) vorinostat and belinostat. Enhanced growth inhibition was also observed when AOH1996 was combined with other HDACi, such as domatinostat and panobinostat. These findings highlight the therapeutic potential of AOH1996 in combination with HDACi, particularly for CTCL, and pave the way for further exploration of this approach in cancer treatment."

Epigenetic controller • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • PCNA

Therapeutic Targeting of Oncogene-induced Transcription-Replication Conflicts in Pancreatic Ductal Adenocarcinoma. (PubMed, Gastroenterology) - "AOH1996 safely and effectively targets TRCs in preclinical PDAC models, with initial clinical evidence supporting its potential for treating chemotherapy-refractory PDAC. Further clinical development is warranted."

Journal • Hepatocellular Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • PCNA

City of Hope Study Demonstrates Proof of Concept for Targeted New Approach to Treat Pancreatic Cancer (Businesswire) - P1 | N=92 | NCT05227326 | "Next, the team tested the approach on two patients whose pancreatic tumors had resisted earlier treatments...The patients experienced up to a 49% shrinkage in their liver metastases after taking the pill twice a day for two months....Overall, the experimental approach was most effective at killing cancer cells with high replication stress, a common phenomenon that occurs when the KRAS gene goes awry in 95% of patients with pancreatic cancer."

P1 data • Pancreatic Cancer

Targeting the "Undruggable": Small-Molecule Inhibitors of Proliferating Cell Nuclear Antigen (PCNA) in the Spotlight in Cancer Therapy. (PubMed, J Med Chem) - "Recent breakthroughs have introduced promising PCNA-targeting candidates, with ATX-101 and AOH1996 entering phase I clinical trials for cancer therapy, garnering academic and industry interest. These achievements provide new evidence for PCNA as a drug target. This article provides insight and perspective on the application of small-molecule PCNA inhibitors in cancer treatment, covering PCNA function, its relationship with cancer, structural modification of small molecule inhibitors, and discovery strategies."

Journal • Review • Oncology • PCNA

AOH1996 Alone or in Combination With Venetoclax With or Without Azacitidine for the Treatment of Patients With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=30 | Not yet recruiting | Sponsor: City of Hope Medical Center

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2

AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition. (PubMed, Exp Hematol Oncol) - "Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells, supporting oxidative metabolism and leukemia stem cell (LSC) growth. The addition of venetoclax (VEN), an FDA-approved Bcl-2 inhibitor, further enhanced AOH's effects, reducing mitochondrial length, FAO, and OXPHOS while improving survival in AML models. While VEN is approved for AML, AOH is under clinical investigation for solid tumors, and our findings support its broader therapeutic potential."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Targeted Protein Degradation • Transplantation • CD34 • CD38 • PCNA

Disrupting Mitochondrial Dynamics and Metabolism in Leukemic Stem Cells through Mitochondrial PCNA Inhibition: The Role of AOH1996 (ASH 2024) - "The BCL-2 inhibitor venetoclax (VEN) has been shown to impact on the oxidative metabolism that supports LSC homeostasis. We demonstrated a better activity when AOH1996 is combined with VEN. While VEN is FDA-approved for AML, AOH1996 is in clinical trials for solid tumors."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Targeted Protein Degradation • CD34 • CD38 • FLT3 • PCNA • PTPRC

AOH1996 for the Treatment of Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=92 | Recruiting | Sponsor: City of Hope Medical Center | Active, not recruiting ➔ Recruiting | Trial completion date: Sep 2024 ➔ Jan 2026 | Trial primary completion date: Sep 2024 ➔ Jan 2026

Enrollment open • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Leiomyosarcoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Osteosarcoma • Ovarian Cancer • Pancreatic Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor • Synovial Sarcoma

Enhancing AOH1996 through structure activity relationship exploration for caPCNA inhibition (AACR 2024) - "The target binding of these analogues was verified by capturing the binary complex of the more polar version of these analogues in the crystal structure. The synthesis, characterization, and detailed biological activities of these promising AOH analogues will be thoroughly described."

Oncology • PCNA

Identification of biomarkers associated with sensitivity to a novel PCNA inhibitor (AOH1996) by CRISPRi screening (AACR 2024) - "We validated the effect of these genes on sensitivity to AOH1996 and identified a panel of target proteins whose up or down-regulation is associated with sensitivity to AOH1996. Some of these proteins are targets of known chemotherapeutic drugs, which may be used in combination with AOH1996 in the clinic."

Biomarker • Oncology • Solid Tumor • PCNA

Enhanced lung cancer treatment using AOH1996, a potent PCNA inhibitor (AACR 2024) - "Initially, EGFR TKIs like gefitinib, erlotinib, afatinib and osimertinib deliver remarkable responses, inducing tumor regression and improving overall survival. In this study, we combine AOH1996 and osimertinib as an innovative approach to treating NSCLC cancers with activating EGFR mutations and find that the drug combination: 1.) enhances the killing of NSCLC cell lines with activating EGFR mutations and acquired resistance to TKIs; 2.) enhances the destabilization of PCNA on chromatin; and 3.) causes changes in the localization and colocalization of PCNA and EGFR. We conclude that the combination of AOH1996 and osimertinib holds much potential as an improved treatment regimen for lung cancer patients with activating EGFR mutations."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PCNA

From proteomic analysis to early investigations of combining inhibitors targeting PCNA and histone deacetylase (AACR 2024) - "Specifically, the histone deacetylase inhibitors belinostat and vorinostat were identified as enriched perturbation signatures. Western blot analysis showed that belinostat decreased protein expression of PCNA, suggestive of mechanistic synergies with AOH1996+belinostat combination therapies. Our proteomic analysis reveals a therapeutic potential of combining AOH1996 and histone deacetylase inhibitors for treating cancer with possibly lower drug dose and toxicities compared to single drug treatment."

Epigenetic controller • Omic analysis • CNS Tumor • Gastrointestinal Cancer • Neuroblastoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • PCNA

AOH1996 for the Treatment of Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: City of Hope Medical Center | Recruiting ➔ Active, not recruiting | N=54 ➔ 6

Enrollment change • Enrollment closed • Oncology • Solid Tumor

AOH1996 for the Treatment of Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=54 | Recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Mar 2024 ➔ Sep 2024 | Trial primary completion date: Mar 2024 ➔ Sep 2024

Trial completion date • Trial primary completion date • Oncology • Solid Tumor