Personalized cancer therapy

Rasoul Salehir_salehi@med.mui.ac.ir

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 ligandbinding to receptor tyrosine kinases (RTKs).

Kinase cascade that transmits signals downstream fromactivated Ras protein to MAP kinase

UGT1A1 polymorphism

• UDP-glucuronosyltransferase 1-1 also known as UGT-1A 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 IRI-based 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 5-FU 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 short-term 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, cost-effective 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