Combinatorial treatment LZTR1 mutant tumors by inhibiting oncogenic substrates

This technology is a combinatorial treatment to target tumors harboring genetic alterations of the tumor suppressor gene Leucine Zipper-like Transcription Regulator 1 (LZTR1).

Unmet Need: Treatment targeting LZTR1 mutations in cancer

The gene LZTR1 encodes an enzyme required for normal protein turnover and mutations in LZTR1 has been found in several cancer types, including glioblastoma, hepatocellular, esophagogastric, colorectal, breast, and more. LZTR1’s substrates include the oncogenes EGFR and AXL, which accumulate in LZTR1 mutant tumors. Given the importance of this gene in tumor progression, combinatorial pharmacological treatments that inhibit EGFR, AXL, or other oncogenic targets of LZTR1 need to be developed to treat cancers involving LZTR1 mutations.

The Technology: Combinatorial treatment targeting LZTR1 alongside oncogene inhibitors

This technology is a combinatorial treatment consisting of inhibitors of various oncogenic LZTR1 substrates, particularly EGFR, AXL, and RIT1. While inhibiting these enzymes alone is not sufficient to treat LZTR1 mutant tumors, this multi-prong approach can significantly reduce tumor burden and prolong survival. Therefore this invention is a targeted therapeutic to cancer patients carrying LZTR1 mutations, as well as for Noonan syndrome and schwannomatosis, both of which involve LZTR1 mutations.

This technology has been validated with mice harboring LZTR1 deleted tumors using combinatorial inhibitors for EGFR and AXL.

Applications:

• Immunotherapy for cancer treatment
• Treatment or preventative for Noonan syndrome and schwannomatosis
• Research model for studying Leucine Zipper-like Transcription Regulator 1 (LZTR1) activity in protein degradation
• Research model for studying EGFR and AXL oncogenic activity

Advantages:

• More effective at targeting LZTR1-mutant cancer growth compared to existing treatment plans
• Provides an approach to precision cancer medicine using existing protein kinase inhibitors
• Sidesteps the need for precise pharmacological inhibitors for master regulators

Lead Inventor:

Antonio Iavarone, MD.

Patent Information:

Patent Issued (WO/2024/103032)

Related Publications:

• Paladino A, D'Angelo F, Noviello TMR, Iavarone A, Ceccarelli M. Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach. J Chem Inf Model. 2021 Apr 26;61(4):1875-1888.
• Ko A, Hasanain M, Oh YT, D'Angelo F, Sommer D, Frangaj B, Tran S, Bielle F, Pollo B, Paterra R, Mokhtari K, Soni RK, Peyre M, Eoli M, Papi L, Kalamarides M, Sanson M, Iavarone A, Lasorella A. LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL. Cancer Discov. 2023 Mar 1;13(3):702-723.

Tech Ventures Reference:

• IR CU23141

• Licensing Contact: Kristin Neuman