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NIH grant 1R43CA314797-01: Novel Non-Mutagenic Ribosome Biogenesis Inhibitors for the Treatment of Small Cell Lung Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Sanjeev Satyal. Award: $404087.
Start: 2026-09-18T00:00:00.
PROJECT SUMMARY
Small cell lung cancer (SCLC) is an aggressive, rapidly growing cancer with a poor prognosis, few novel
treatments on the horizon, and no cures that can overcome treatment resistance or cancer recurrence. Multiple
molecular subtypes of SCLC are known to be driven by the MYC oncogene, which promotes malignant
proliferation and metastasis by serving as master regulator of ribosome biogenesis (RiBi). Ribosome biogenesis
is an integral process essential for the vast protein synthesis demand of rapidly growing, aggressive tumors, and
has been an appealing target for cancer therapies. Unfortunately, prior attempts at targeting RiBi in tumors have
been stymied by significant off-target toxicity, such as the induction of DNA damage. Palade Therapeutics has
identified next-generation, potent RiBi inhibitors that do not cause significant DNA damage using highthroughput
screening (HTS) of > 350,000 small molecules. HTS was conducted via Ribo-SNAP, a novel,
patented technology enabling dynamic monitoring of ribosome assembly, function, and turnover at single-cell
resolution in living human cells. Initial Ribo-SNAP screening revealed 30 high-quality hits, from which 2 were
prioritized as lead candidates based upon their ability to preferentially inhibit RiBi and induce apoptosis without
causing DNA damage in cancer cells by targeting RNA polymerase I (Pol I), an essential, primary component of
the RiBi pathway. Molecular experiments have identified that the MYC and Pol I pathways will be most sensitive
to RiBi inhibition in SCLC subtypes which will likely translate to enhanced efficacy and specificity, leading to an
improved therapeutic index. In this Phase I SBIR project, Palade Therapeutics will evaluate the efficacy of its
lead RiBi inhibitor candidate in an array of SCLC cell lines, using these insights to validate efficacy and identify
opportunities optimize the pharmacokinetic properties and minimize off-target toxicity in vitro. Finally, Palade
Therapeutics will identify the maximum therapeutic dose of its lead RiBi inhibitor and demonstrate in vivo proof
of concept of this new therapeutic modality. These in vivo studies are necessary to detect any unexpected
adverse effects or potential pharmacokinetic deficiencies of RiBi inhibitors that cannot be identified solely with in
vitro systems. This project will demonstrate the potential of RiBi inhibition to provide an enhanced therapeutic
index in SCLC via selective inhibition of ribosome biogenesis and improve patient outcomes by delivering
enhanced therapeutic efficacy while minimizing off-target toxicity.document fetched 2026-09-27 02:45