Satya Narayan, PhD

My research program at the University of Florida College of Medicine is dedicated to the discovery and development of first-in-class small-molecule therapeutics for aggressive and therapy-resistant malignancies, specifically Triple-Negative Breast Cancer (TNBC) and Colorectal Cancer (CRC). Central to our mission is the pharmacological activation of historically undruggable or overlooked molecular targets to restore tumor-suppressive signaling and induce selective apoptosis. By integrating synthetic medicinal chemistry with advanced human-centric modeling—including Patient-Derived Xenografts (PDX)—we aim to bridge the gap between basic laboratory discovery and clinical application.

1. Development of DH20931 as a First-in-Class Therapeutic for Triple-Negative Breast Cancer: In this project our goal is to advance translational oncology and drug discovery, specifically focusing on identifying and validating novel molecular targets for therapy-resistant malignancies such as Triple-Negative Breast Cancer (TNBC) and Colorectal Cancer (CRC). By bridging the gap between basic mechanistic biology and clinical application, the lab aims to develop first-in-class small-molecule therapeutics that offer higher efficacy with reduced systemic toxicity compared to conventional treatments.

A cornerstone of our current research is the characterization of Ceramide Synthase 2 (CerS2) as a potent, druggable target in aggressive cancers. Central to this work is the development of DH20931, a first-in-class CerS2 agonist (activator). Unlike traditional inhibitors, DH20931 induces a power surge of pro-apoptotic, very long-chain ceramides (VLCCs). This work, recently detailed in the journal Molecular Cancer Therapeutics, provides a comprehensive validation of the two-hit hypothesis for cancer cell death. This mechanism operates by simultaneously triggering lipotoxic endoplasmic reticulum (ER) stress through the ATF4-CHOP pathway and inducing mitochondrial calcium overload. The latter is facilitated by a novel physical interaction between CerS2 and the ER calcium channel IP3R1, which DH20931 enhances to drive lethal mitochondrial dysfunction.

Beyond individual drug mechanisms, the lab is actively investigating strategies to overcome chemoresistance. Recent studies demonstrate that DH20931 acts as a powerful chemosensitizer, significantly increasing the vulnerability of TNBC cells to Doxorubicin. This synergy allows for a substantial fivefold reduction in the necessary dose of Doxorubicin while maintaining robust anti-tumor activity, offering a promising clinical path to mitigate the debilitating side effects often associated with standard chemotherapy regimens.

To ensure high clinical predictability, we utilize advanced human-centric modeling, including 3D Matrigel spheroid assays and Patient-Derived Xenograft (PDX) models. These systems allow the lab to study the interaction between lipid signaling and DNA repair pathways—such as Base Excision Repair (BER)—within the context of the complex human tumor microenvironment. Through these innovative approaches, the Narayan Lab continues to push the boundaries of precision medicine, seeking to provide transformative therapeutic options for patients with the most challenging cancer diagnoses.

2. Discovery of First-in-Class PP2A Activators as a Therapeutic Strategy for Drug-Resistant Colorectal Cancer: This research focus centers on the pharmacological reactivation of Protein Phosphatase 2A (PP2A), a major serine/threonine phosphatase and tumor suppressor that is frequently functionally inactivated in gastrointestinal cancers. Our program focuses on overcoming the clinical challenge of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) resistance in colorectal cancer (CRC) by restoring PP2A’s regulatory control over oncogenic signaling.

As documented in our work published in iScience and the Journal of Medicinal Chemistry, we have identified and optimized first-in-class small-molecule PP2A agonists, including NSC49L and the second-generation lead PPA24. These activators function by directly stimulating PP2A activity, which in turn downregulates the AKT1/mTOR/4EBP1 signaling axis and selectively inhibits the translation of the cell-cycle inhibitor p21. This mechanistic intervention is critical because we discovered that p21 acts as a molecular brake on apoptosis by binding to procaspase 3; by suppressing p21 translation, our PP2A activators sensitize previously resistant CRC cells to TRAIL-mediated apoptosis.

Building upon these findings, our most recent studies utilized molecular modeling and fragment-based design to develop PPA24, a highly potent agonist with superior binding affinity for the PP2A catalytic subunit α. PPA24 not only induces oxidative stress and decreases c-Myc expression but also shows powerful synergy with standard agents like gemcitabine and cisplatin. To improve clinical delivery, we have developed PPA24-encapsulated nanoformulations that demonstrate significant anti-tumor efficacy in xenograft models with a favorable safety profile. This project establishes PP2A activation as a transformative therapeutic strategy for patients with advanced, drug-resistant colorectal cancer.