Methods of Using Modified Cytotoxins to Treat Cancer

NU 2019-135

INVENTORS

Nathan Gianneschi*

SHORT DESCRIPTION

Methods for treating cancers that overexpress fatty acid uptake proteins using small-molecule cytotoxic drugs conjugated to long-chain fatty acid moieties. See also NU2022-111.

BACKGROUND

While prior work (under NU2022-111) demonstrated that lipid-mimicking cytotoxin prodrugs with fatty acid chains could reduce tumor size in xenograft models and allow higher tolerable doses than conventional formulations, the mechanism of action and optimal clinical applications remained unclear. Cancer cells can selectively uptake certain chemotherapeutics through passive or active targeting, but the specific targeting mechanism of these fatty acid-conjugated cytotoxins had not been elucidated. The discovery that many metastatic cancers and aggressive tumor types characteristically overexpress fatty acid transporter proteins like CD36 to fuel their enhanced metabolic demands suggested a potential active targeting mechanism that could be exploited therapeutically.

ABSTRACT

This technology identifies methods of treating cancer by administering cytotoxic drugs conjugated to long-chain fatty acid-like hydrophobic moieties specifically for treating cancers that overexpress fatty acid uptake proteins, such as CD36. Blocking CD36 with sulfosuccinimidyl oleate (SSO) significantly reduces the cytotoxicity of fatty acid-conjugated paclitaxel (ODDA-PTX) in HT-1080, MCF-7, and HepG2 cell lines, while having minimal effect on unconjugated paclitaxel, proving that CD36-mediated cellular uptake is the primary mechanism of action rather than simple albumin binding. The methods include both monotherapy with these modified cytotoxins and combination therapy regimens where the fatty acid-conjugated drug is administered with immunomodulating agents, exploiting the compounds' ability to induce immunogenic cell death that primes tumors for improved response to subsequent immunotherapy.

APPLICATIONS

Targeted treatment of metastatic cancers where CD36 and other fatty acid uptake proteins are overexpressed during metastatic progression, enabling selective delivery of cytotoxic payloads to aggressive, therapy-resistant tumor populations.
Personalized oncology protocols allowing stratification of cancer patients based on CD36 expression levels and enabling rational treatment selection based on tumor metabolic phenotype.
Sequential combination immunotherapy where fatty acid-conjugated cytotoxins are administered first, followed by checkpoint inhibitors, anti-CD47 antibodies, or TLR agonists, converting immunologically "cold" tumors into "hot" tumors responsive to immunotherapy.

ADVANTAGES

Active tumor targeting through metabolic exploitation of CD36 and related fatty acid transport proteins overexpressed on cancer cells, representing more targeted approach compared to simple albumin-binding or passive accumulation.
Selective efficacy against aggressive cancer phenotypes as CD36 overexpression correlates with metastatic potential, cancer stem cell characteristics, and therapy resistance across multiple cancer types, while sparing CD36-low normal tissues.
Broader therapeutic window through dual mechanisms combining reduced systemic toxicity from albumin binding with enhanced tumor uptake via CD36-mediated active transport.

PUBLICATION

Callmann et al. Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin. J Am Chem Soc. 141 (30): 11765-11769 (2019).

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