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Conquest - Timeline of Discovery: Lung Cancer

Making the Connection 2001-2008

Timeline of Discovery: Lung Cancer

Date: April 20, 2010

CRF Investigator Shyam Biswal

Cigarette exposure facility is constructed to study smoke-induced lung cancer and
uncover protein biomarkers for the cancer. Cancer-causing constituents are quantified,
including carbon dioxide, nicotine and acrolein in smoke.

Biswal’s work revealed new information about smoking related carcinogens and the cellular changes that ultimately result in cancer. His findings are reported in two scientific
journals and at the Society of Toxicology annual meeting. This work led to a lung cancer
project in the National Cancer Institute Specialized Program Of Research Excellence.
2003 The facility allows researchers to identify and test chemopreventive agents that block the negative impact of smoke on cells. They also have begun to pinpoint specific
cellular changes that could serve as biomarkers for the early detection of lung cancer.
A National Institute Health investigator initiated research grant was funded.

The protein Nrf2, studied in the exposure facility and found in animal models to alter
the lungs response to cigarette smoke, is target for cancer prevention drug trials.

Another gene, Keap1 gene is identified as NRF2’s co-conspirator. Keap1, lets cells
know when the toxins are removed, shutting down NRF2 and stopping the cell
cleansing process. He finds NRF2 directs proteins to absorb pollutants and chemicals
and then pumps them out, clearing cells of toxins.

Lung cancer cells corrupt the process. An altered Keap1 gene keeps the NRF2 gene
active and pumping out cancer-attacking drugs before they can get into cancer cells.
This work earned additional grants from NIH and the Flight Attendant Medical
Research Institute.

JHU has been granted two international patent applications. The first invention is
going through the second year of sponsored project with a pharmaceutical company
which has an option to license from JHU. The second invention has led to a university
faculty start up company AImmune, Inc., located in the JHMI Science & Technology
Park. This company is in negotiation with JHU for licensing the invention for commercialization.

Biswal tests a compound that blocks NRF2 in lung cancers with Keap1 mutations, in
combination with anticancer drug carboplatin to target the cancer while blocking treatment
resistance. A clinical trial has been funded by NCI to improve chemotherapy in
lung cancer targeting the Keap1 mutation.

Survival from lung cancer, caused by cigarette smoking, has been difficult to
achieve because resistance to current cancer drugs develops. Each year in
the U.S. nearly half a million people die of smoking-related diseases. Keap1
mutations and the NRF2 pathway are implicated in lung cancer and chronic
obstructive pulmonary disease.

A cigarette exposure facility is constructed to study smoke-induced lung cancer
and uncover protein biomarkers for the cancer. The protein Nrf2 is identified
and found to pump out carcinogens, including therapeutic anticancer drugs.

Biswal, working with Geoffrey Gumin from University of Maryland, begin screening
1280 compounds that can knock down NRF2 in patients. The best candidate will be
used in lung cancer patients to block resistance to chemotherapy

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