# Defining mechanisms of thalidomide analog resistance

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $266,668

## Abstract

PROJECT SUMMARY
Thalidomide and its analogs, lenalidomide and pomalidomide, have revolutionized the treatment of patients with
multiple myeloma (MM) and other hematologic malignancies. However, therapeutic resistance still limits their
efficacy and represents a critical unmet medical need. These drugs work through a unique mechanism leading
to the targeted degradation of oncoproteins. Because only the protein levels of the drug targets are affected,
they have been difficult to study using conventional technologies. We developed a novel targeted mass
spectrometry assay to measure these proteins and now propose in Aim 1 to use this assay to study the
relationship between the level of thalidomide analog targets and the development of lenalidomide resistance in
patients. In an orthogonal study to identify mediators of thalidomide analog resistance downstream of substrate
degradation I have performed multiple genetic screens in a MM cell line and have identified the retinoic acid
receptor alpha and the nuclear corepressor as potential mediators of lenalidomide resistance. In Aim 2 I propose
to further characterize these genes and their roll in mediating the response to thalidomide analogs in MM cells.
Collectively, this work will further outline two major pathways of resistance to a clinically important class of drugs
and shed new light on methods to overcome resistance. The applicant, Dr. Adam Sperling, is an oncologist at
the Dana-Farber Cancer Institute (DFCI). He spends 80% of his time in translational research and 20% in clinical
practice caring for patients with cancer. He has outlined a five-year career development plan to meet his goal of
becoming an independent investigator in translational research. Dr. Sperling has assembled an Advisory
Committee of internationally recognized experts to provide scientific and career mentorship. He has established
collaborations with experts in cancer epigenetics, mass spectrometry, and applied biostatistics to provide
experimental advice and specific training in the field. Dr. Sperling will conduct this research at the DFCI and
leverage the exceptional research and teaching environment at the DFCI, Harvard, and the Broad Institute. The
Dana-Farber Cancer Institute, which harbors an outstanding research community and has a long track record
for successful mentorship of independent physician scientists, is an ideal environment for completion of these
experiments and the realization of Dr. Sperling’s long-term career goal of being an independent physician-
scientist.

## Key facts

- **NIH application ID:** 10876390
- **Project number:** 5K08CA252174-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Adam Sperling
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $266,668
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876390

## Citation

> US National Institutes of Health, RePORTER application 10876390, Defining mechanisms of thalidomide analog resistance (5K08CA252174-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10876390. Licensed CC0.

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