# A Novel ULK1 Pathway as a New Therapeutic Target in Melanoma

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $408,596

## Abstract

Project Summary/Abstract
Melanoma is a highly fatal malignancy for which immunotherapy approaches have been shown to be effective.
While immune checkpoint blockade (ICB) has transformed the treatment of advanced melanoma, the majority of
patients are resistant to therapy initially or respond but then relapse. Thus, efforts to identify mechanisms of
resistance to checkpoint inhibitors and approaches to overcome primary and acquired resistance are warranted.
Surprisingly, type II interferon (IFN) signaling pathways and expression of IFN-stimulated genes (ISGs) in
melanoma patients have been shown to correlate with either response or resistance to ICB treatment, in a
context-dependent manner. While IFN-inducible genes are required for effector function of tumor-reactive T
cells and response to ICB in melanoma, IFN is also known to induce expression of immunosuppressive genes
and chronic IFN signaling promotes acquired resistance to ICB. This dual role of IFN signaling supports the
need to identify means to selectively regulate its effects in order to promote cytotoxic T lymphocyte (CTL) activity
without promoting immunosuppression. We have recently discovered that ULK1 (Unc-51-like kinase 1) controls
activation of unique IFN signaling events and transcription of specific IFN-induced genes involved in the control
of immune responses. Importantly, our preliminary studies show that genetic or pharmacologic targeting of ULK1
in melanoma cells represses IFN-induced expression of immunosuppressive genes without affecting expression
of immunostimulatory ones, and high levels of ULK1 expression correlate with poor survival in melanoma
patients. The goal of this project is to determine if targeting ULK1 blocks IFN-dependent immunosuppressive
effects and related biological responses, while promoting IFN-mediated CTL activity against melanoma. Aim 1
will define the specific role of ULK1 on IFN-induced expression of immunosuppressive genes and on cytotoxic
T lymphocyte activity against melanoma. It includes generation of specific knockout melanoma cells, and
evaluation of ULK inhibition on T-cell mediated tumor killing in vitro. Aim 2 will define the role of ULK1 in ICB-
mediated immune responses in melanoma. The effects on melanoma tumor growth of genetic or
pharmacological inhibition of ULK1 in combination with immune checkpoint inhibitors will be examined in vivo.
Additionally, the expression and activation of ULK1 will be correlated to clinical responses in melanoma patients
receiving ICB therapy. The results of this project will advance our understanding on how specific IFN signaling
events affect the success of immune responses against melanoma and will provide the basis for novel targeted
approaches involving combination of specific regulators of IFN signaling with immune checkpoint inhibitors for
the treatment of melanoma.

## Key facts

- **NIH application ID:** 10044661
- **Project number:** 1R21CA245447-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Diana Nora Vaz Saleiro
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,596
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044661

## Citation

> US National Institutes of Health, RePORTER application 10044661, A Novel ULK1 Pathway as a New Therapeutic Target in Melanoma (1R21CA245447-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10044661. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*