# Project 2: Transcriptional Dynamics and Temporal Reprogramming During Radiation Treatment

> **NIH NIH U54** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $183,964

## Abstract

SUMMARY
Radiation therapy (RT) is the single most utilized anti-cancer agent; nearly 70% of all cancer patients will receive
radiation at some point in their cancer journey, and RT plays a crucial role in almost half of all cancer cures. The
sequencing of the human genome, completed nearly 20 years ago, followed by the large scale cancer
sequencing effort in The Cancer Genome Atlas (TCGA) have provided an unprecedented understanding of
cancers in the primary and metastatic setting. In those same years, medical oncology has undergone three major
phase transitions: targeted therapies have changed the way we think many diseases with specific actionable
mutations; immunotherapy has revolutionized the treatment of many of those without; and antibody-drug
conjugates have increased the specificity of our cytotoxics. RT treatment decision making, however, has not
seen these same changes from biological influences, instead having relied on advances in medical physics and
computer science to drive our advances. While the number of trials has ballooned in radiation oncology of late,
spurred on by encouragement, and funding, from pharmaceutical companies interested in the synergy between
novel (and profitable) compounds in the form of immune checkpoint inhibitors and antibody-drug-conjugates,
with radiation, our understanding of the relative benefits and best choices for individual patients has not seen
the same increases. In fact, we have struggled to parse out the differences between these novel combinations
and standard chemoradiotherapy in phase II trials, largely because of the combinatorial nature of our trials, and
the sheer number of open questions. In this project, we seek to make headway toward personalizing radiation
therapy treatment choices. Using our experience in using gene signatures to predict individual patient radiation
benefit, together with expertise in radiomics and genomics, we will use 4 carefully crafted cohorts to dissect out
the relative contribution of radiation, standard chemotherapy, the immune checkpoint inhibitor Nivolumab and
the antibody-drug conjugate Sacituzumab govitecan. Having chosen two disease sites which benefit from high
(but not uniform) cure rates with standard cisplatin-radiation combination therapy (bladder and head and neck),
we have structured two investigational trials to compare to standard therapy. In each trial (bladder, with SG+RT,
and HNSCC with ICI+RT) we will compare and contrast the temporal changes in tumor transcriptomic and
mutational state change in primary tumor tissue and surrogates from shed cells and circulating tumor DNA. The
‘ground truth’ of these genomics through time will be married to high temporal density radiomics features to allow
for translation and generalization to all patients treated with modern technique. Through these complimentary -
omic modalities, we aim to leverage our experience in creating signatures of therapeutic response to admit
personalized treatment choice in the up...

## Key facts

- **NIH application ID:** 10896485
- **Project number:** 5U54CA274513-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jacob Gardinier Scott
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $183,964
- **Award type:** 5
- **Project period:** 2022-09-14 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896485

## Citation

> US National Institutes of Health, RePORTER application 10896485, Project 2: Transcriptional Dynamics and Temporal Reprogramming During Radiation Treatment (5U54CA274513-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896485. Licensed CC0.

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