Heat shock protein

Studies and Therapeutic Targeting of Heat Shock Proteins in Lung Cancer

2006

Targeted Therapeutics Research Award

Funded equally by LUNGevity Foundation, American Lung Association of Metropolitan Chicago, American Lung Association National Office, and the family of Harriet Meyers

Ravi Salgia, MD, PhD

University of Chicago

Chicago

Heat shock proteins (HSPs) are a class of proteins that are central to the survival of cells, in particular those under stress. Inhibiting HSPs makes cells very sensitive to cell death under stressed conditions (e.g., during chemotherapy). Dr. Salgia is studying the role of HSP27 in lung cancer to develop targeted therapies that are effective against it.

Key words

Non-small cell lung cancer (NSCLC)

Small cell lung cancer (SCLC)

Squamous cell lung cancer

Targeted therapy

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Novel C-terminal Hsp90I with isoform selectivity will function as selective anti-cancer agents in the treatment of lung cancers

2009

Targeted Therapeutics Research Award

LUNGevity Foundation/The University of Kansas Cancer Center Research Grant

George A. Vielhauer, PhD

University of Kansas Medical Center

Kansas City

HSP90, a heat shock protein, protects cancer cells from chemotherapy. Dr. Vielhauer’s laboratory is developing novel targeted therapy that selectively blocks HSP90 and kills lung cancer cells.

Key words

Heat shock protein

Targeted therapy

Read more about Novel C-terminal Hsp90I with isoform selectivity will function as selective anti-cancer agents in the treatment of lung cancers

Targeting KRAS-mutant NSCLC through inhibition of MTOR and Hsp90

2013

Career Development Award

Timothy F. Burns, MD, PhD

University of Pittsburgh Cancer Institute

Pittsburgh

Dr. Burns is working on targeted therapy for NSCLC patients with mutations in a gene called KRAS, using a new class of drugs.

Research Summary

Lung cancer is the leading cause of cancer death in the United States and worldwide. In non-small cell lung cancer (NSCLC), a protein called KRAS often becomes inappropriately turned on and causes a tumor to grow. Patients with KRAS-mutated lung cancer have a poor prognosis and no current therapies target this critical oncogene. Our goal is to develop novel therapies for patients with KRAS mutant lung cancer. In this proposal, we focus on a therapy that can inhibit multiple signaling pathways downstream of KRAS that are required for KRAS mutant tumors to grow. We have found in a clinical trial that some of the KRAS mutant tumors shrink when treated with a novel Hsp90 inhibitor, ganetespib. In Aim 1 of this grant we will identify what makes some KRAS mutant tumors respond initially to ganetespib and then become resistant. These studies will identify targeted therapeutics agents that could be combined with ganetespib to overcome resistance to ganetespib alone. Furthermore, we have recently shown that the combination of an Hsp90 inhibitor, ganetespib, and an mTOR inhibitor is effective in KRAS mutant tumor cell lines. In Aim 2, we will examine candidate biomarkers of response to this combination so that we can test these biomarkers in the third aim of our grant, a Phase I/II clinical trial of the combination of ganetespib and an mTOR inhibitor in patients with KRAS mutant NSCLC. This translational approach will allow us to target this combination to the patients who are likely to respond.

Technical Abstract

A significant fraction of NSCLC have mutant KRAS which predicts poor response to cytotoxic therapy and portends a poor prognosis. Despite the discovery of the first mutation in the KRAS oncogene in NSCLC over two decades ago, there are no current therapies targeting this critical oncogene. In this proposal we explore a novel and exciting therapeutic strategy to target KRAS-mutant NSCLC through the combination of Hsp90 and mTOR inhibition. We have preclinical evidence suggesting that the combination of ganetespib and an mTOR inhibitor may be an effective therapeutic strategy for patients with KRAS- mutant NSCLC. In Aim 1, we will define resistance mechanisms to single-agent ganetespib in KRAS- mutant NSCLC. The identification of resistance mechanisms to single-agent ganetespib will reveal novel pathways that we can then target in combination with an Hsp90 inhibitor. In Aim 2, we will test the hypothesis that activation of the mTOR pathway through alterations in STK11 or PI3KCA mutations will predict response to the combination. Finally, in Aim 3 we will translate our studies to the clinic in a phase I/II trial of the combination of ganetespib and an mTOR inhibitor in patients with advanced KRAS-mutant lung adenocarcinoma. Importantly, we will have correlative studies looking at response in subpopulations of KRAS-mutant tumors that are hyperactive for the mTOR pathway (STK11, PIK3CA mutations). This translational approach will allow us to identify biomarkers that we can use to effectively target this combination to the patients with greatest chance to benefit from this therapy.

Key words

Acquired resistance

Adenocarcinoma

Biomarker or biomarker testing

Heat shock protein

KRAS

mTOR

Non-small cell lung cancer (NSCLC)

PI3 kinase

Targeted therapy