lo 3Targeting PcG as a treatment of cancer

What is the name of the FDA-approved EZH2 inhibitor for lymphoma?

Tazemetostat

What is the objective response rate of Tazemetostat in EZH2 mutant follicular lymphoma?

69% (95% CI 53.8-81.1)

What is the objective response rate of Tazemetostat in EZH2 wild-type follicular lymphoma?

51% (23-49.1)

What is the median duration of response for Tazemetostat in EZH2 mutant lymphoma?

19.5 months

What is the median duration of response for Tazemetostat in EZH2 wild-type lymphoma?

11.4 months

What adverse events were seen with Tazemetostat in lymphoma trials?

Thrombocytopenia, anemia (grade 3 or worse)

In what year did the FDA grant accelerated approval to Tazemetostat for follicular lymphoma?

June 18, 2020

What secondary EZH2 mutations were identified in resistant cells?

Y111L and Y661D

Do EZH2 inhibitor resistance mutations cooperate?

Yes, they cooperate to confer resistance

What was the objective response rate of Tazemetostat in BAP1-mutant mesothelioma?

Only 2/61 patients had partial response (no complete responses)

What was the disease control rate of Tazemetostat in BAP1-mutant mesothelioma at week 12?

54% (95% CI 42-67)

What is the name of the EZH2 inhibitor from Epizyme?

EPZ005687

How selective is EPZ005687 for EZH2 versus other methyltransferases?

Greater than 500-fold selectivity

What is the selectivity of EPZ005687 against EZH1?

50-fold selectivity

What cellular effect does EPZ005687 have on mutant lymphoma cells?

Apoptotic cell killing

Does EPZ005687 affect proliferation of wild-type cells?

Minimal effects on proliferation of wild-type cells

What is the objective response rate of Tazemetostat in epithelioid sarcoma/MRT?

15% (9 of 62 patients)

What was the disease control rate at 32 weeks for Tazemetostat in MRT?

26% (16 of 62 patients)

What was the median progression-free survival for Tazemetostat in MRT?

5.5 months

What was the median overall survival for Tazemetostat in MRT?

19.0 months

What combination trial is currently underway for Tazemetostat in MRT?

Tazemetostat plus doxorubicin in front-line setting (NCT04204941)

What compound targets EZH2-EED interaction?

Astemizole / DC-PRCzin-01

What type of compound is MS177?

PROTAC

What does UNC1999 target?

EZH1/2 (catalytic inhibitor)

What type of inhibitor is A-395?

Allosteric inhibitor (targets EED)

What PRC1 component does RB-3 target?

RING1B (nucleosome-RING1B interaction inhibitor)

What PRC1 component does PTC596 target?

PCGF4 (BMI1) through hyper-phosphorylation

What does UNC3866 target?

CBX4/7 chromodomain

What effect does H3K27M have on EZH2 inhibitor efficacy?

H3K27M inhibits PRC2, making EZH2 inhibitors potentially effective

Is EZH2 a good drug target in BAP1 mutant cancers?

Poor drug target because BAP1 promotes PRC2 repression

What does the mechanistic research on BAP1 highlight?

Importance of mechanistic research in human health and disease

What happened with Tazemetostat in BAP1-mutant mesothelioma phase 2 trials?

No complete responses, only 2 partial responses out of 61 patients

What does oncogene addiction mean in relation to EZH2 mutations?

Mutant cells show critical dependency on EZH2 enzymatic activity for proliferat