Download Promising targeted drugs for NSCLC

Promising targeted drugs for
NSCLC
Peter Berzinec
Specialised Hospital of St Zoerardus Zobor
Teaching Base of Slovak Medical University
Nitra, Slovakia
The woods are lovely, dark, and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.
Robert Frost Stopping by Woods on a Snowy Evening
The hallmarks of cancer
Six hallmark capabilities proposed
in the 2000 perspective.
Emerging hallmarks
and enabling characteristics
in the 2011 perspective.
Mutant p53 gain of function
Hanahan D, Weinberg R A. Hallmarks of cancer: the next generation. Cell. 2011, 144: 646-674.
Solomon H. et al. J. Pathol. 2011, 225: 475–478
Tumor supressor gene (antioncogene) P53
Function of WT P53
Damage of DNA
P53 activates:
Gadd45, mdm2
bax, p21, IGF-BP3
p53
Apoptosis
p53
p53
G1 arrest
Increased synthesis
P53 and therapeutic strategies
• Gene therapy (virus-based introduction of intact cDNA copy
- based on adenovirus - Adp53)
• Gene therapy + chemotherapy
• Gene therapy + radiotherapy
• Adenovirus p53 vaccine therapy
• P53 pathway
- TKIs: Hdm-2/p53 interaction inhibitors (CGM097)
WEE 1 kinase inhibitors (AZD1775, MK 1775)
Autologous dendritic cell-adenovirus p53 vaccine
Cancer stem cell (CSC) and lung cancer
Identification:
• Resistance to toxic compounds
– Increased DNA repair
– Overexpression of anti-apoptotic proteins
– Overexpresion of drug transporters
– Quiescent nature
• Stem cell markers
– CD133+, ALDHhigh, CD44+
M.M. Ho, et al. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer
cells. Cancer Res. 2007, 67, 4827–4833
A.Koren et al. Cell Oncol. 36, 4, 265-75.
“Recent studies performed in the Thoracic Oncology Laboratory, SB/NCI, demonstrate that under exposure
conditions potentially achievable in clinical settings, mithramycin diminishes stem cell gene expression and
markedly inhibits growth of lung and esophageal cancer and MPM cells in vitro and in vivo. These finding add
to other recent preclinical studies demonstrating impressive anti-tumor activity of mithramycin in epithelial
malignancies and sarcomas that frequently metastasize to the thorax”.
Sponsor: NCI
Driving mutations in NSCLC - AC
Lung Cancer Mutation Consortium, driving mutations with targeted therapies
ASCO 2011 (Kris M et al.)
ASCO 2013 (Johnson BJ et al.)
Lung Cancer Mutation Consortium, driving mutations with targeted therapies
ASCO 2013 (Johnson BJ et al.)
WCLC 2013 (Kris M.)
OST
Target/M+: targeted therapy used vs unused
OST
Most common mutation
Kris M. WCLC 2013
Targets and targeted therapies/trials in LCMC Project
Kris M. WCLC 2013
Kris M. http://www.elseviercme.com/516/courses/lesson-i-targeting-met-lung-cancers (opens: APR 2014 – exspires: APR 2015:
MASTER PROTOCOL SQC, targets and targeted therapies
Herbst R. ASCO Post. November 1, 2013
Patient with metastatic SQ NSCLC with long-term
survival (4 years + )
Therapy (lines):
1. gemcitabine, cisplatin, necitumumab, 2. docetaxel, 3. erlotinib, 4. oral vinorelbine