Lee Krug M.D.

This grant is being fully funded by Elliot’s Legacy, through the Uniting Against Lung Cancer Grant Program.

Lay Description

SCLC has been treated with the same chemotherapy drugs, etoposide and cisplatin, for the past 30 years. While this chemotherapy treatment often works well initially and can result in remissions, the disease usually develops resistance to the chemotherapy so it grows back quickly and then becomes even more difficult to treat. We propose to test a new class of drugs, called heat shock protein 90 (Hsp90) inhibitors, for the treatment of small cell lung cancer (SCLC). Heat shock proteins interact with many other proteins in the cell that are responsible for cell growth and for changing it into a cancer cell. They protect these proteins during times of stress, and thereby allow the cell to survive. A majority of SCLC cells lack a particular gene, called Retinoblastoma (RB), which is important for controlling normal cell growth. Laboratory colleagues from our institution have found that treating SCLC cells lacking RB with Hsp90 inhibitors makes the cells stop growing normally and instead quickly die. In experiments using Hsp 90 inhibitors to treat SCLC cell lines (in vitro experiments), and models with SCLC tumors (in vivo experiments), SCLC cell growth slows down and tumors get smaller. We would like to 1) further study SCLC cell lines and models with SCLC tumors by treating them with both chemotherapy and the Hsp 90 inhibitor NVP-AUY-922 to determine the effectiveness of the combination, and 2) conduct a clinical research trial in which patients with metastatic SCLC will be treated with standard chemotherapy plus weekly NVP-AUY-922 to confirm that this drug combination is safe in humans. In the future, based on these results, a much larger clinical study will be conducted in which patients will be randomized to receive chemotherapy alone or together with an Hsp90 inhibitor. If successful, this would establish a new standard treatment for this disease.

Scientific Abstract

The heat shock proteins (Hsp), including Hsp 90, are molecular chaperones important for conformational support and functional activation of “client proteins” necessary for normal cell growth. In addition, Hsp90 chaperones support malignant transformation via stabilization of various onco-proteins. Pre-clinical studies performed at our institution indicate that Hsp90 inhibition will selectively induce cell cycle arrest in mitosis followed by apoptosis in RB-null or RB mutant tumor cells. The majority of SCLC tumors possess a retinoblastoma (RB) null phenotype, and thus this observation provides an opportunity to exploit its tumor biology. Additional work performed here demonstrates SCLC cell growth inhibition in vitro and tumor regression in nude mice in vivo when treated with Hsp90 inhibitors. We propose combining Hsp90 inhibitors with standard chemotherapy to break the therapeutic stalemate which has existed in SCLC for 3 decades. We propose 1) preclinical studies to evaluate proper dose and drug-sequencing when Hsp90 inhibitor NVP-AUY-922 (Novartis, Inc.) is given in combination with etoposide and cisplatin, and 2) a phase I trial of standard chemotherapy in combination with weekly NVP-AUY-922 for untreated patients with extensive stage small cell lung cancer . These data would ultimately lead to a randomized trial of etoposide/cisplatin alone or in combination with an hsp90 inhibitor, with the hopes of improving on our currently inadequate standard of care.