UAB30 / UAB University - Birmingham - LARVOL DELTA

Targeting the RXR Pathway for the Prevention of Triple Negative Breast Cancer. (PubMed, Cancer Prev Res (Phila)) - "In this study, we tested whether nuclear retinoid X receptor (RXR) ago-nists, IRX4204 and 9cUAB30, which have been evaluated in clinical trials, could prevent the de-velopment of ER-negative and triple-negative breast cancers (TNBCs). Biomarker analysis revealed that delayed tumors arising after IRX4204 treatment had decreased Ki-67 expression and increased infiltration of cytotoxic T-cells. Our pre-clinical study data support the further evaluation of use of RXR agonists for the prevention of TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • HER-2

Modeling Epithelial Homeostasis and Perturbation in Three-Dimensional Human Esophageal Organoids. (PubMed, Biomolecules) - "In the HOME0-grown organoids, IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media."

Journal • Eosinophilic Esophagitis • Gastrointestinal Disorder • Immunology • Oncology • EGF • IL13 • TGFB1

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1 | N=27 | Terminated | Sponsor: National Cancer Institute (NCI) | N=39 ➔ 27 | Active, not recruiting ➔ Terminated; Inadequate Accrual Rate

Enrollment change • Trial termination • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

RXR agonist, 9cUAB30 impacts epigenetic regulations to achieve chemoprevention of UVB-induced Skin cancer by altering global miRNA profiling (AACR 2024) - "In summary, this profiling of miRs in UVB-induced BCC and SCC represents the underlying epigenetic mechanisms that regulate various signaling pathways in these cancers. Our data also show the critical role of miRs responsive to UAB30 treatment in cancer chemoprevention."

Clinical • miRNA profiling • Basal Cell Carcinoma • Genito-urinary Cancer • Melanoma • Non-melanoma Skin Cancer • Oncology • Prostate Cancer • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma • HIF1A • MicroRNA 30c • MIR133B • MIR196B • MIR21 • MIR210 • MIR218 • MIR26A1 • MIR30B • MIR324 • MIR328 • MIR495 • MIR96

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid. (PubMed, PLoS One) - "Thus, the biological effects of UAB30 and UAB110 are mediated through the AF-2 domain of RXRα with minimal side effects in human epidermis. As ATRA levels are known to be reduced in certain epithelial pathologies, treatment with UAB30 and UAB110 may represent a promising therapy for normalizing the endogenous ATRA concentration and signaling in epithelial tissues."

Journal

A Biomarker Evaluation Trial of UAB30 in Renal Transplant Recipients at High Risk for Non-melanoma Skin Cancer (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: University of Alabama at Birmingham | N=84 ➔ 0 | Trial completion date: Aug 2025 ➔ Aug 2023 | Recruiting ➔ Withdrawn | Trial primary completion date: Aug 2024 ➔ Aug 2023

Biomarker • Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Genetic Disorders • Melanoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • Transplantation • CCND1

Retinoid X receptor agonists enhances type I systemic and intratumoral immunity, but enhanced tumor prevention, with the HER2-IGFBP2-IGF1R plasmid vaccine in two mouse mammary tumor models (SITC 2023) - "Background Bexarotene and 9cUAB30 are oral retinoid X receptor (RXR) agonists which inhibit proliferation in breast cancer. There was no evidence by IHC of antigen expression loss with sequential RXR agonist with the vaccine. Conclusions The RXR agonists have an immunostimulatory role with plasmid cancer vaccines, but further modification of the immune environment may be needed for prevention vaccines."

IO biomarker • Preclinical • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • CD4 • CD8 • CSF2 • FOXP3 • HER-2 • IFNG • IGFBP2 • PD-1

A Biomarker Evaluation Trial of UAB30 in Renal Transplant Recipients at High Risk for Non-melanoma Skin Cancer (clinicaltrials.gov) - P1/2 | N=84 | Recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: Aug 2024 ➔ Aug 2025 | Trial primary completion date: Aug 2023 ➔ Aug 2024

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Genetic Disorders • Melanoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • Transplantation • ATM • BCL2 • CASP3 • CCND1 • CD4 • CD8 • CHEK1 • FOXP3 • GABRP • IL10 • IL22 • PCNA • RAD51

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1 | N=39 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2023 ➔ Jun 2024

Trial completion date • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CASP3 • ER • HER-2

Epigenetic mechanism underlying pathogenesis of skin photo-damage and actinic keratoses (AACR 2023) - "9cUAB30 treatment attenuates growth of human SCC xenograft tumors in highly immune-suppressed mice, a response which was significantly more profound when the drug was administered with a survivin inhibitor, LQZ-7I. These translational studies demonstrate that UVB-induced cutaneous BRD4 drives AK pathogenesis and their progression to invasive SCCs."

Late-breaking abstract • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • BIRC5 • BRD4 • CDK4 • CXCL9 • E2F1 • IL33 • MMP13 • SOCS3

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1 | N=39 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Feb 2023 ➔ Jun 2023

Trial completion date • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CASP3 • ER • HER-2

Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics. (PubMed, J Biol Chem) - "Here, we examined the mechanism of action of next-generation rexinoids UAB110 and UAB111 that are more potent in vitro than UAB30 and the FDA-approved Targretin. UAB110 binding also showed increased dynamics towards the dimer interface through the Helix 8 and Helix 9 regions. These data suggest that UAB110 and UAB111 are potent activators of RXR-RAR signaling pathways but accomplish activation through different molecular responses to ligand binding."

Journal

PIM Kinase Inhibition Results in Neuroblastoma Differentiation (AAP-NCE 2022) - "Cells were treated with the pan-PIM inhibitor, AZD1208, a novel rexinoid agonist, UAB30, or a combination of pre-treatment with AZD1208 for 72 hours followed by 72 hours of UAB30 treatment. Neuroblastoma cells treated with the combination of a PIM inhibitor and a rexinoid agonist demonstrated a more differentiated phenotype. These findings are potentially mediated through increased HOXC9. These data support the need for further studies of the role of PIM kinase inhibition as a therapeutic strategy to improve RA-induced differentiation, potentially mitigating disease relapse in high risk neuroblastoma."

CNS Tumor • Immunology • Neuroblastoma • Oncology • Solid Tumor • PIM1

A Biomarker Evaluation Trial of UAB30 in Renal Transplant Recipients at High Risk for Non-melanoma Skin Cancer (clinicaltrials.gov) - P1/2 | N=84 | Recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: Aug 2022 ➔ Aug 2024 | Trial primary completion date: Aug 2022 ➔ Aug 2023

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Genetic Disorders • Melanoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • Transplantation • ATM • BCL2 • CASP3 • CCND1 • CD4 • CD8 • CHEK1 • FOXP3 • GABRP • IL10 • IL22 • PCNA • RAD51

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1 | N=38 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting | Trial primary completion date: Dec 2022 ➔ Jun 2022

Enrollment closed • Trial primary completion date • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CASP3 • ER • HER-2

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1 | N=41 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Feb 2022 ➔ Dec 2022 | Trial primary completion date: Feb 2022 ➔ Dec 2022

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CASP3 • ER • HER-2

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1; N=45; Recruiting; Sponsor: National Cancer Institute (NCI); Suspended ➔ Recruiting

Clinical • Enrollment open • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • MRI

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1; N=45; Suspended; Sponsor: National Cancer Institute (NCI); Recruiting ➔ Suspended

Clinical • Trial suspension • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • MRI

[VIRTUAL] Retinoid X receptor agonists enhances Th1 antigen-specific and polyfunctional T cells with the HER2-IGFBP2-IGF1R vaccine (AACR 2021) - "Bexarotene and 9cUAB30 are highly selective oral retinoid X receptor (RXR) agonists with anti-proliferative activity in breast cancer. HER2-IGBP2-IGF1R vaccination after 200 mg/kg 9cUAB30 increased antigen-specific polyfunctional T cells to 7.6±2.0% (p=0.01) and antigen-specific CD8 polyfunctional T cells to 17.6±4.1% (p=0.003). These data indicate that RXR agonists have an immunostimulatory role with multi-antigen cancer vaccines and may augment the anti-tumor activity of vaccines."

Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • CD4 • CD8 • CSF2 • HER-2 • IFNG • IGFBP2 • IL10 • IL2 • TNFA

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1; N=45; Recruiting; Sponsor: National Cancer Institute (NCI); Trial primary completion date: Jul 2021 ➔ Feb 2022

Clinical • Trial primary completion date • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Retinoid 9cUAB30 in Producing a Biologic Effect in Patients With Early Stage Breast Cancer (clinicaltrials.gov) - P1; N=45; Recruiting; Sponsor: National Cancer Institute (NCI); Trial primary completion date: Apr 2021 ➔ Jul 2021

Clinical • Trial primary completion date • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Novel second-generation rexinoid induces growth arrest and reduces cancer cell stemness in human neuroblastoma patient-derived xenografts. (PubMed, J Pediatr Surg) - "6-Me decreased oncogenicity and reduced cancer cell stemness of neuroblastoma PDXs, warranting further exploration of 6-Me as potential novel therapy for neuroblastoma."

Clinical • Journal • Neuroblastoma • Oncology • Solid Tumor • CD133 • NANOG • POU5F1 • SOX2

Stability of the Retinoid X Receptor-α Homodimer in the Presence and Absence of Rexinoid and Coactivator Peptide. (PubMed, Biochemistry) - "The complexes of UAB110 and UAB111 are each more stable than the UAB30 complex by 8 kJ/mol due to enhanced hydrophobic interactions in the binding pocket because of their larger end groups. This increase in thermodynamic stability positively correlates with their improved RXR activation potency. Thermodynamic measurements are thus valuable in predicting agonist potency."

Journal

Rewiring Tumor Cell State in Cancer Therapy: Comment on '9-cis-UAB30, a Novel Rexinoid Agonist, Decreases Tumorigenicity and Cancer Cell Stemness of Human Neuroblastoma Patient-Derived Xenografts' by 'Elizabeth Beierle et al.' (PubMed, Transl Oncol) - No abstract available

Clinical • Journal • Neuroblastoma • Oncology • Solid Tumor

Novel retinoic acid derivative induces differentiation and growth arrest in neuroblastoma. (PubMed, J Pediatr Surg) - "These results indicate a potential therapeutic role for this novel rexinoid in neuroblastoma treatment."

Journal • Neuroblastoma • Oncology • Solid Tumor