Epigenetic Therapy for Thoracic Malignancies

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Despite impressive results from preclinical in-vitro experiments and diverse murine tumor models, poor biodistribution and systemic toxicities prevent optimal, chronic administration of epigenetic agents necessary to reprogram thoracic malignancies in clinical settings. To further optimize epigenetic priming of pulmonary malignancies, we have conducted preclinical studies to examine the pharmacokinetics and potential efficacies of the DNA demethylating agents, decitabine (DAC) azacytidine (AZA) administered by aerosolization techniques. We developed a unique immunocompetent murine pulmonary metastasis model using cancer stem cells isolated from the highly lethal, syngeneic Lewis lung cancer (LLC) line. We observed impressive and very favorable pharmacokinetics and obvious clinical activity of these aerosolized agents without systemic toxicities. A phase I/II clinical trial examining the toxicities and potential efficacy of AZA administered via inhalation techniques in combination with durvalumab as induction therapy in patients with operable NSCLC is expected to open in the next several months. An additional trial evaluating alternating cycles of DAC and AZA in combination with immunomodulatory agents in subjects with multifocal GGOs (preinvasive lung adenocarcinomas) is in preparation for institutional review. No such clinical efforts are currently underway elsewhere in the world. We are collaborating with Dr. Stephen Belinsky from the University of New Mexico Comprehensive Cancer Center to bring a novel dry, powder formulation of Azacitidine to NCI for a first-in-humans trial in subjects with NSCLC. This formulation could allow home administration of aerosolized AZA. Although cancer-testis (CT) - also referred to as cancer -germline antigens are expressed in a variety of human malignancies, immune responses to these proteins are uncommon in thoracic oncology patients due to low level, heterogeneous antigen expression, deficient antigen processing/presentation, and local as well as systemic immunosuppression. We and others have demonstrated that CT-genes and genes encoding proteins involved in antigen processing and presentation can be derepressed in cancer cells but not normal cells by epigenetic regimens. Following positive results of a phase 2.5 First-in-Human trial evaluating the use of a cancer cell lysate vaccine as adjuvant therapy in patients with primary thoracic malignancies or tumors metastatic to the lungs, we have written a new protocol using this lysate vaccine (which was developed in our lab) as adjuvant therapy for patients with lung or esophageal cancers and mesothelioma rendered NED by SOC, as well as individuals with subclinical thoracic malignancies not warranting SOC intervention. The lysate vaccine will be administered with the IL-15 super-agonist N-803. The presence of subclinical mesotheliomas with reproducible alterations in DNA methylation in subjects with germline BAP1 mutations provides unique opportunities to investigate if epigenomic interventions can abort progression of these malignancies to lethal disease states. We have initiated a series of small, focused phase II trials (accrual targets of 10-12 patients per trial) examining if oral epigenetic agents can abort progression of subclinical tumors to radiographically evident, life-threatening malignancies. These drugs include oral decitabine/cedazuridine (NCT05960773) and APG-115 (IRB001605; NCT06654050) which target the DNA methylation machinery; an additional protocol evaluating NBM-BMX- a selective HDAC8 inhibitor which activates and stabilizes p53 is undergoing institutional review. These oral agents have been selected for evaluation based on a series of peer reviewed publications from our lab demonstrating that disruption of these pathways occurs very early during epigenetic reprogramming of human mesothelial cells isolated from subjects with germline BAP1 mutations. We anticipate that analyses of biospecimens from our surveillance and current treatment trials will help guide future interventions in subjects with germline BAP1 mutations.