# Phenotypic marker-guided development of selective antimetastasis therapeutic leads

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $609,809

## Abstract

The lack of effective treatment against cancer metastasis is in large part due to the complexity of the metastatic
transformation process and incomplete understanding of the key underlying mechanisms. The list of genes and
pathways associated with carcinogenesis is growing and anti-cancer agents targeting single gene activities have
reached clinics and shown primary tumor growth inhibition. However, these agents fall short in effectively treating
metastasis, leading to poor long-term patient survival and reinforcing the challenge of cancer complexity. It has
long been a clinical practice to grade the levels of malignancy based on morphological changes of tumor cells
and tissues, where a high-grade cancer generally correlates with poor patient outcomes, suggesting cancer
specific pathognomonic features can be used as readouts for the malignant potential of cancer tissues. Here we
utilize a “top-down” approach, in which specific subcellular pathognomonic structures unique to metastatic
potential are used as surrogate markers for malignancy. We reason that such cellular substructures should
reflect the complex and unique malignant properties better than any single gene or gene product. These
structures not only provide an in vitro experimental platform (cell lines) to investigate the key factors important
for cancer metastasis (and subsequent in vivo validations), but also serve as a phenotypic marker for anti-cancer
drug development. To this end, we have validated the perinucleolar compartment (PNC), a nuclear body, as
such a marker for cancer cell malignant behavior.
PNCs are highly prevalent in metastatic tumors and PNC prevalence positively correlates with disease
progression and inversely correlates with patient outcomes in several cancers. Using PNC prevalence reduction
as a phenotypic marker for metastasis in a high-content screen, we developed the phase I clinical candidate
metarrestin, a potent PNC inhibitor for a large array of cancer cell lines. Metarrestin inhibits invasion in vitro,
blocks metastatic development in three mouse models of human cancers, and extends survival of mice in a
metastatic pancreatic cancer xenograft model without discernable adverse effects.
This proposal describes a two-pronged approach for the development new anti-metastasis therapeutic leads.
We have identified eEF1A2 as a molecular target for metarrestin and will use inter-disciplinary, complementary
approaches to leverage interactions with eEF1A2 to develop more potent PNC prevalence inhibitors as next
generation therapeutic leads. In parallel, we will use PNC prevalence as a phenotypic readout to interrogate
additional structurally distinct high-throughput screening hits. These hits have been vetted for PNC activity,
counterscreened for cytoxicity and DNA binding, and confirmed to possess efficacy in in vitro migration and
invasion experiments. Both complementary approaches capitalize on the knowledge gained from the
development of metarrestin and facilitat...

## Key facts

- **NIH application ID:** 10892829
- **Project number:** 5R01CA269967-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Kevin J. Frankowski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $609,809
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892829

## Citation

> US National Institutes of Health, RePORTER application 10892829, Phenotypic marker-guided development of selective antimetastasis therapeutic leads (5R01CA269967-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10892829. Licensed CC0.

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