WHAT ARE THE MAJOR DRAWBACKS OF CONVENTIONAL CHEMOTHERAPEUTIC

WHAT ARE THE MAJOR DRAWBACKS OF CONVENTIONAL CHEMOTHERAPEUTIC AGENTS? 1 2

1 POOR SELECTIVITY LOW THERAPEUTIC INDEX

2 DRUG RESISTANCE

TARGETED AGENTS IN ANTICANCER CHEMOTHERAPY

ONCOGENE ACTIVATION

TUMOR SUPPRESSOR INACTIVATION 1) Point mutation p 53

TUMOR SUPPRESSOR INACTIVATION 1) Point mutation: p 53, BRCA 1 etc. 2) Deletion 3) Epigenetic silencing

Locus 9 p 21

TUMOR SUPPRESSOR INACTIVATION 1) Point mutation: p 53, BRCA 1 etc. 2) Deletion 3) Epigenetic silencing 4) Protein-protein interactions

TUMOR SUPPRESSOR INACTIVATION Protein-protein interactions

Table 1 Examples of oncogene addiction: studies in mice Weinstein IB and Joe AK (2006) Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy Nat Clin Pract Oncol 3: 448– 457 10. 1038/ncponc 0558

Table 2 Examples of oncogene addiction: studies in human cancer cell lines Weinstein IB and Joe AK (2006) Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy Nat Clin Pract Oncol 3: 448– 457 10. 1038/ncponc 0558

Table 3 Clinical evidence of oncogene addiction Weinstein IB and Joe AK (2006) Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy Nat Clin Pract Oncol 3: 448– 457 10. 1038/ncponc 0558

MODELS OF ONCOGENE ADDICTION

Two genes (‘A’ and ‘B’) are said to be synthetic lethal if mutation of either gene alone is compatible with viability but simultaneous mutation of both genes causes death.

% B inhibition

effetti lievi Cellula normale PTEN attività PI 3 K/Akt/m. TOR INIBITORI DI m. TOR Cellula tumorale PTEN attività PI 3 K/Akt/m. TOR

Cellula normale BRCA 1 SSB DSB BER riparazione HR BER Instabilità genomica HR Cellula tumorale riparazione

INIBITORI DI PARP Cellula normale BRCA 1 SSB DSB SSB BRCA 1 Cellula tumorale BER HR DSB riparazione INIBITORI DI PARP BER DSB HR HR HR riparazione

SOPRAVVIVENZA Cellula normale Rb blocco attività E 2 F VELENI DELLA TOPO II Rb attività E 2 F Cellula tumorale espressione gene A espressione gene topoisomerasi II espressione gene B espressione gene C

HOW CAN WE SELECTIVELY TARGET TUMOR RELEVANT DEFECTS? INHIBIT GENE EXPRESSION AS-ODN si. RNA INHIBIT PROTEIN FUNCTION m. Abs Small molecule inhibitors