Targeting LASP1, eIF4A1, eIF4B, and CXC4 with Modulators for treating cancer

Description:

Project ID: D2019-32

Background:
Breast cancer (BC) is a heterogeneous disease and is the second leading cause of death in women among the cancer mortalities. With the new estimates in 2019, 3 out of 10 women will develop BC in her lifetime and 1 in 7 will succumb to BC. Mortality in BC patients is mainly due to metastasis to the lungs, bone, and brain. Triple-negative breast cancer (TNBC) is a highly aggressive form of BC with increased risk of relapse, drug resistance, and metastases. CXCR4 has been identified to be one of the major chemokine receptors involved in breast cancer metastasis, and LIM and SH3 Protein 1 (LASP1) are key mediators in CXCR4-driven invasion. Durable or pathological complete response (pCR) is low in metastatic TNBC (mTNBC) patients. Resistance to standard neoadjuvant chemotherapy (NACT) is mainly due to a small subset of cells in the tumor called breast cancer stem-like cells (BCSCs). BCSCs are capable of self- renewal, proliferation, plasticity, and immune regulation. These properties mediate primary tumor progression, metastasis, and resistance to chemotherapy. Effective and safe drugs for advanced mTNBC are needed. Targeted therapies such as PARP inhibitors though effective initially, become resistant due to RAD52 in BCSCs. Overall, there is an unmet need for identifying novel targeted combination therapies against mTNBC.

Invention Description:
Researchers at the University of Toledo have developed a novel method for reducing translation of oncogenic proteins in cancer cells, the method comprising contacting cancer cells with a first agent, wherein the first agent is an inhibitor of a first target selected from the group consisting of: eIF4A and its downstream effectors, LASP1, CXCR4, CXCL8, CXCL12, contacting the cancer cells with a second agent, wherein the second agent is an inhibitor of a second target selected from the group consisting of: eIF4A, LASP1, CXCR4, CXCLB, CXCL12, CXCL8,; wherein the first agent and the second agent are administered in amounts effective to reduce translation of oncogenic proteins in the cancer cells.  In certain embodiments, the first target is different from the second target. Combination of first agent with second agent effectively inhibits survival and proliferation of TNBC cells and BCSCs derived from TNBC cells. The first and second agent can effectively be combined with NACT involving taxanes, anthracyclines and platinum drugs.

Application:
Treatment of all types of cancer including breast cancer and its difficult-to-treat subtypes such as triple-negative breast cancer. 

 

Advantages:

  1. Highly efficacious against both therapy-naïve and drug-resistant TNBC cells.
  2. Effectively targets BCSCs derived from TNBC cells.
  3. Can be effectively be combined with NACT involving taxanes, anthracyclines and platinum drugs.

IP Status: PCT pending

Publications: Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness. Sridharan et al. - Frontiers in Oncology - 2019

Patent Information:
Category(s):
Oncology
For Information, Contact:
Lokesh Mohan
Licensing Associate
The University of Toledo
419-530-6231
lokeshwar.mohan@utoledo.edu
Inventors:
Dayanidhi Raman
Cory Howard
John Nemunaitis
F. Charles Brunicardi
Shi-He Liu
Amit Tiwari
Keywords:
Cancer
CXCL12
CXCL8
CXCLB
CXCR4
eIF4A
LASP1
mTNBC
NACT
pCR
TNBC
Triple negative breast cancer