Mats Ljungman Ph.D.

Recipient of the LUNGevity Foundation/Joan's Legacy Research Grant. Funded equally by Joan's Legacy and the LUNGevity Foundation.

Lay Description

Lung cancer is the number one cancer killer claiming more than 160,000 lives annually in the United States. Small cell lung cancer which accounts for about 20% of all lung cancers, (SCLC) is one of the most aggressive forms with patients having less than a 5% 5-year survival if diagnosed with advanced stage disease. Since current anti-cancer treatments do not work well (or at all) against SCLC, a better understanding of the unique physiology of this type of cancer is desperately needed to bring about the development of a new generation of drugs and treatments. One of the major genes in the development and progression of SCLC is a gene called myc. In healthy tissues, this gene is regulated in a very precise manner so that cells can live and grow normally. However, in SCLC the myc gene is abnormally active resulting in the aggressive growth and spread of these cancer cells. In some cancers very high MYC protein levels are due to that the DNA region encoding the myc gene has been amplified so that each cells produce a lot more of the MYC protein. However, in most cases MYC is over produced by some as yet unknown mechanism. The aim of this pilot research project is to investigate the mechanisms by which MYC is overproduced in SCLC. A better understanding of these mechanisms would lay the foundation for the design of novel therapies aimed at shutting off the abnormally high production of MYC and inhibiting the growth of these tumors.

Scientific Abstract

The oncogene myc is frequently overexpressed in small cell lung cancers (SCLC) and this overexpression is thought to contribute to the aggressive phenotype of SCLC. While gene amplification is responsible for MYC overexpression in some tumors, overexpression of myc frequently occurs in the absence of gene amplification. The mechanism(s) for the amplification-independent overexpression of myc are not fully understood. We will in this pilot grant determine whether this overexpression is due to increased synthesis or stability of myc mRNA and what role microRNAs may play in this regulation using a panel of 9 SCLC cell lines and two normal cell lines. In Aim #1, we will utilize a newly developed approach called SSD (for Steady-state, Synthesis and Degradation of RNA) to determine whether the elevated steady state mRNA levels of c-myc and L-myc found in a panel of SCLC cell lines without myc gene amplification are due to changes in the synthesis and/or stability of c-myc mRNA. In Aim #2, we will assess whether any abnormal steady state levels of microRNAs are due to alterations in the synthesis or degradation of the microRNA using the SSD technique coupled with real-time RT-PCR arrays. We will also assess the protein levels of IMP-1 and LIN28, two proteins that may be involved in the regulation of myc. By better understanding the molecular mechanisms regulating myc overexpression in SCLC, we foresee the identification of novel targets for which new therapies could be developed.