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Finding a Cure for
Untreatable Non-Small Cell Lung Cancer
Sreenath V. Sharma,
PhD, Massachusetts General Hospital Cancer Center
FUNDING
AGENCIES:
The LUNGevity Foundation, Mass General Hospital , Roberta M.
Bartram Fund of Goldman Philanthropic Partnerships, the James M.
Hughes Fund of Goldman Philanthropic Partnerships
Lung cancer is the leading cause of cancer-related deaths
worldwide. Non-Small Cell Lung Cancer (NSCLC) accounts for a
majority (80%) of cases of lung cancers. Overall, fewer than
10% of lung cancer patients are alive 5 years after initial
diagnosis and this number drops to less than 5% in individuals
with advanced-stage NSCLC. Even the most aggressive
conventional chemotherapy is excessively toxic and only
marginally improves survival rates. Thus, there is a tremendous
need to develop better therapies for lung cancer treatment.
Recent studies have identified Epidermal Growth Factor Receptor
(EGFR) as a protein that is found at high levels in NSCLC. This
formed the basis for the development of drugs that inhibit the
EGFR for the treatment of NSCLC. Two such drugs, namely,
Gefitinib/Iressa (AstraZeneca) and Erlotinib/Tarceva (OSI
Pharmaceuticals, Genentech and Roche), received “fast track”
approval from the US Food and Drug Administration (FDA) for use
as drugs of last resort in patients with advanced NSCLC. The
focus of this research is on these two drugs. Early experience
from clinical trials of these drugs indicated that they are able
to create dramatic clinical responses in about 10% of treated
patients - responses that could not be achieved by any other
treatments available to date. However, 90% of cases failed to
respond and even the 10% of cases that show response to the drug
were prone to developing resistance to the drug after some
time.
Dr.
Sharma and his co-researchers observed that sensitive lung
cancer cells that become resistance to these two drugs, as well
as lung cancer cells that were insensitive to them in the first
place are effectively killed by combination of these drugs and a
well known anti-malaria drug. This combined drug approach might
expand considerably the range of lung cancers that can be
effectively treated by Iressa and Tarceva. In addition, adding
the anti-malaria drug might allow physicians to reduce the
dosage of Iressa and Tarceva to substantially decrease toxicity
and the cost of treatment. Finally, it is possible that other
tumors besides lung cancer may also be treatable by the
anti-malaria drug combination approach.
Research Project
Business Plan/Budget
TITLE:
Chemo-sensitizing Non Small
Cell Lung Cancer to Gefitinib & Erlotinib
FUNDING AGENCIES:
LUNGevity, Mass
General, Roberta M. Bartram Fund of Goldman Philanthropic
Partnerships, the James M. Hughes Fund of Goldman Philanthropic
Partnerships
PROJECT CODE #: SS093005
FUNDING PERIOD:
10/1/05-9/30-07
TOTAL OPERATING BUDGET:
$185,000
SPECIFIC AIMS AND
OBJECTIVES OF RESEARCH PLAN
First Quarter (Year 01):
Research Objective 1:
Generation of Gefitinib and Erlotinib-resistant cell lines from
PC-9, H-3255 and NCI-H1650 NSCLC cells.
Research Objective 2:
Characterization of Gefitinib and Erlotinib-resistant NSCLC cell
lines with respect to EGFR status and fold reduction in
sensitivity to Gefitinib and Erlotinib.
Second Quarter (Year 01):
Research Objective 3:
Examine the effect of Gefitinib and Erlotinib on Intracellular
Vesicular Compartment Acidification in sensitive, insensitive
and resistant cell lines.
Research Objective 4:
Examine the ability of Chloroquine to sensitize Gefitinib- and
Erlotinib-insensitive and resistant cell lines to killing by
Erlotinib.
Third Quarter (Year 01):
Research Objective 5:
Examine the ability of other Intracellular Vesicular Compartment
Acidification Inhibitors besides Chloroquine to sensitize
Gefitinib- and Erlotinib-insensitive, Gefitinib-resistant and
Erlotinib-resistant cell lines, to killing by Gefitinib and
Erlotinib.
Research Objective 6:
Examine the effect of Intracellular Vesicular Compartment
Acidification inhibitors on EGFR autophosphorylation, EGFR
stability and tyrosine phosphorylation of other cellular
proteins.
Fourth Quarter (Year 01):
Research Objective 7:
Examine the effect of Intracellular Vesicular Compartment
Acidification inhibitors on signaling down-stream of the EGFR to
ERK1/2, STAT-5 and PI-3K/Akt.
Research Objective 8:
Examine the ability of inhibitors of specific pro-survival
signal transduction pathways, either singly or in combination,
to synergize with Gefitinib or Erlotinib to kill NSCLC cells.
First Quarter (Year 02):
Research Objective 9:
Examine the effect of Intracellular Vesicular Compartment
Acidification inhibitors on EGFR trafficking by
Immunofluorescence Microscopy.
Research Objective 10:
Examine the effect of Intracellular Vesicular Compartment
Acidification inhibitors on Gefitinib- and Erlotinib-mediated
killing of human tumor cells other than those derived from
NSCLC.
Second Quarter (Year 02):
Research Objective 11:
Examine the effect of Intracellular Vesicular Compartment
Acidification inhibitors on Gefitinib- and Erlotinib-mediated
killing of cells that are EGFR deficient.
Research Objective 12:
Fluorescence Associated Cell
Sorting of NCI-H1650 (DE746-A750) cells treated with Gefitinib
or Erlotinib.
Third Quarter (Year 02):
Research Objective 13:
Assessment of Gefitinib or Erlotinib sensitivity of Lysotracker
positive and Lysotracker Negative NCI-H1650 cells
Research Objective 14:
Examination of the role of IVC acidification inhibitors on
Gefitinib- and Erlotinib-mediated killing of Lysotracker
positive and Lysotracker Negative NCI-H1650 cells
Fourth Quarter (Year 02):
Research Objective 15a:
Examination of Lysotracker positive and Lysotracker Negative
NCI-H1650 (DE746-A750)
cells with respect to EGFR autophosphorylation, EGFR stability
and tyrosine phosphorylation of other cellular proteins.
Research Objective 15b:
Examination of Lysotracker positive and Lysotracker Negative
NCI-H1650 (DE746-A750)
cells with respect to signaling down-stream of the EGFR to
ERK1/2, STAT-5 and PI-3K/Akt. |
