Cancer Therapy via Simultaneous Non-apoptotic Cell Death Mechanisms

Project ID: D2018-15 

Background

Most current cancer therapies rely on agents that trigger apoptotic (programmed) cell-death pathways. During
treatment, tumors can acquire mutations that diminish apoptotic responses and become chemoresistant, often
accompanied by increased drug efflux and enhanced DNA repair. This resistance contributes to therapeutic failure,
particularly in recurrent and aggressive cancers. There is a need for therapies that eliminate cancer cells through
non-apoptotic cell-death mechanisms.

Invention Description

Researchers at The University of Toledo have developed a family of small-molecule compounds and methods to
induce cancer cell death via methuosis, autophagy, or a combination of both ("methuophagy"). 

In published studies, representative compounds induce rapid accumulation of large, fluid-filled cytoplasmic vacuoles

derived from macropinosomes (methuosis hallmark) togetherwith alterations in autophagic/lysosomal signaling

(e.g., autophagy markers and acidic/lysosomal compartments).Cell death is described as non-apoptotic and

independent of necroptosis, and activity is reported in multiple cancer types including apoptosis-refractory settings.

Applications

• Standalone anti-cancer agents for tumors refractory to apoptosis-inducing chemotherapies.
  • Chemo-adjuvants/chemosensitizers to restore or enhance response to cytotoxic agents in resistant cancers
  (e.g., in combination settings described with mitoxantrone/doxorubicin).
  • Drug-delivery enablement through macropinocytosis/vacuolization to enhance intracellular uptake of otherwise
  membrane-limited payloads (e.g., macromolecules and particulate delivery systems).
  • Prodrug and lysosome-targeted strategies leveraging reported increases in lysosomal activity/biogenesis.
  • Pharmacological probes for studying macropinocytosis, vacuole dynamics, lysosomal trafficking, and
  non-apoptotic cell-death biology.

Advantages

• Defined small-molecule scaffold with broad chemical space (multiple heterocyclic linkers and aryl/heteroaryl

variants) to support lead optimization.

• Reported activity across multiple tumor types (e.g., colon cancer, triple-negative breast cancer, glioblastoma,

ovarian, prostate, and pancreatic models).

• Combination potential: described sensitization of resistant cancer cells to antineoplastic agents in published

studies.

• Early tolerability signals reported in zebrafish and repeat-dose mouse studies at tested conditions.

IP Status: US 11,406,626, 11,986,467, 12,485,114B2