Transcript Poursina Conference

Personalized cancer therapy
Rasoul Salehi
[email protected]
Personalized therapy
• Personalized cancer medicine is based on
increased knowledge of the cancer mutations
and availability of agents that target altered
genes or pathways.
Personalized cancer therapy
GENOMIC MEDICINE
• Is the use of information from genomes and
their derivatives (RNA, proteins, and
metabolites) to guide medical decision
making.
• It is a key component of personalized
medicine
BENEFIT – TOXICITES/RATIO
Colorectal cancer genetic testing
Cell signalling pathways in colorectal cancer
Operational Wnt signaling pathway
• KRAS mutations (which occur in approximately
45–50% of patients with CRC) is now routine
clinical practice and anti-EGFR treatment is
only given to patients who are KRAS wild type.
This is the first true use of personalized
medicine in CRC.
Activation of Ras following ligand
binding to receptor tyrosine kinases (RTKs).
Kinase cascade that transmits signals downstream from
activated Ras protein to MAP kinase
UGT1A1 polymorphism
• UDP-glucuronosyltransferase 1-1 also known as UGT1A is an enzyme encoded by the human UGT1A1 gene
• UGT-1A is a UDP-glucuronosyltransferase, (UDPGT), an
enzyme that transforms small lipophilic molecules, such as
steroids, bilirubin, hormones and drugs into water-soluble,
excretabl metabolites
UGT1A1 genotyping and irinotecan (IRI)
toxicity in advanced CRC cases
• Prospective analysis of UGT1A1 genotyping for predicting
toxicities in advanced colorectal cancer (aCRC) treated with
irinotecan (IRI)-based regimens: Interim safety analysis of a
Japanese observational study.
• Conclusions: Considering UGT1A1 genotype along with other
clinical factors is important for managing pts undergoing IRIbased regimens. Our presentation will provide analysis of data
from more than 1000 pts
DPYD mutation analysis
• 5-fluorouracil (5-FU) is a fluoropyrimidine drug
and is the most frequently used
chemotherapeutic drug in the treatment of
colorectal cancer and other solid tumors.
• The dihydropryrimidine dehydrogenase (DPD)
enzyme, encoded by the DPYD gene, is
responsible for the degradation and inactivation
of greater than 80 percent of 5-FU.
DPYD mutation analysis
• Reduced DPD activity can lead to the accumulation
of active 5-FU metabolite (FdUMP), which leads to 5FU sensitivity. The consequences of increased
sensitivity could be increased efficacy and/or severe
dose-related toxicity.
• DPYD mutations are associated with decreased DPD
activity, leading to production of proportionately
higher than normal amounts of FdUMP and
increased risk for dose-related 5-FU sensitivity.
Methylenetetrahydrofolate reductase
(MTHFR) polymorphism
• MTHFR is involved in the metabolism of folate and
forms the reduced folate cofactor needed for TS
(thymidylate synthase ) inhibition.
• Mutations in the MTHFR gene lead to reduced
MTHFR enzyme activity, which increases intracellular
folate metabolites and may increase the rate of
activity of TS.
Methylenetetrahydrofolate reductase
(MTHFR) polymorphism
• The primary target for 5-FU is TS, encoded by the TYMS
gene.
• TS catalyses the methylation of deoxyuridine
monophosphate (dUMP) to deoxythymidine
monophsophate (dTMP), which is essential for DNA
replication.
• An active metabolite of 5-FU, fluorodeoxyuridine
monophosphate (5-FdUMP) prevents DNA synthesis by
forming stable complexes with TS with folate as a co-factor,
thus preferentially blocking the production of dTMP in
cancer cells.
ERCC1, XRCC1, GSTP1 polymorphisms
• excision repair cross-complementation 1 & 2
(ERCC1 & 2) , X-ray cross-complementing 1
(XRCC1), genotypes are independently associated
with poor progression-free survival and shortterm survival
• Glutathione S-transferase P1 (GSTP1) is a subclass
of Glutathione S-transferases (GSTs) that directly
participates in the detoxification of platinum
compounds and is an important mediator of both
intrinsic and acquired resistance to platinum
• platinum complexes react in vivo, binding to
and causing crosslinking of DNA, which
ultimately triggers apoptosis.
• Lynch syndrome or HNPCC
• MSI & IHC testing
Human MMR Genes
MLH1 (3p21)
MSH2 (2p16)
PMS2 (7p22)
MSH6 (2p16)
PMS1 (2q31-33)
MSH3 (5q3)
MSI TESTING
MSI is detected by comparing PCR amplicons of the microsatellite loci . Unstable loci
appear as extra products in tumor tissue compared to normal tissue.
• Prognosis – Several studies have shown that MSI tumors have a
more favorable prognosis and are less prone to lymph node and
systemic metastasis.
• Prediction of response to 5-FU and irinotecan therapy – Current
data suggests that stage II MSI tumors do not benefit (and might
actually be harmed) by 5-FU therapy and MSI tumors may be more
responsive to irinotecan than microsatellite stable (MSS) tumors.
• Detection of Lynch Syndrome - The role of MSI as a genetic marker
of Lynch Syndrome is well established. Both MSI detection and IHC
are highly sensitive methods for the identification of a defective
MMR system and guide clinicians towards informative, costeffective genetic testing.
Hereditary cancer prevalence control
• Positive family history
• Appropriate genetic testing
• Family members screening, based on
information obtained from index case genetic
testing
• PGD could be provided to those who are
inherited the mutation
• Healthy, disease free offsprings resulting in
gradual eradication of hereditary cancers
• Thanks for your kind attendance
and attention