PTC299 IS A NOVEL DHODH INHIBITOR FOR USE IN TREATMENT OF AML
Author(s): ,
Marla Weetall
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
Josephine Sheedy
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
Bansri Furia
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
Christopher Trotta
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
John Baird
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
Edward O'Mara
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
Robert Spiegel
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
Kylie O'Keefe
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
Isabella Smallera-Birns
Affiliations:
PTC Therapeutics,South Plainfield,United States
,
Gautam Borthakur,
Affiliations:
MD Anderson,Texas,United States
,
Kensuke Kojima
Affiliations:
Saga University,Saga,Japan
Pande Amitkumar
Affiliations:
PTC Therapeutics,South Plainfield,United States
EHA Library. Weetall M. Jun 15, 2019; 266621; PS1004
Marla Weetall
Marla Weetall
Contributions
×
Abstract

Abstract: PS1004

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
PTC299 is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis that had previously been in clinical trials for treatment of solid tumors. Pyrimidine nucleotides can be generated either by de novo synthesis or the salvage pathway in which pyrimidine nucleotides are obtained from the diet. Resting cells typically acquire adequate pyrimidine nucleotides from the salvage pathway. Rapidly proliferating cells, however, are dependent on the de novo synthesis of pyrimidine nucleotides.

Aims
The goal of these studies was to identify the mechanism by which PTC299 inhibits leukemia cell proliferation and to demonstrate efficacy in a range of cell and mouse models of leukemia.

Methods
In vitro studies utilized fresh blood from AML patients that were treated ex vivo with PTC299 and analyzed by flow cytometry.  In vivo were done using mouse models of AML.

Results
In vitro, AML cells differentiated as shown by increased monocyte markers (e.g. CD14) or showed reduced viability. Consistent with the activity observed in vitro, PTC299 reduced the growth of leukemia cells in mouse models using human cell lines or patient-derived xenografts (PDX models).  When combined with cytotoxic agents and other therapeutics used in treatment of AML, PTC299 enhanced activity in multiple mouse models of leukemia.

Conclusion
The favorable pharmaceutical properties of PTC299 together with an extensive PH1/2 clinical experience in solid tumors with PTC299 make this a promising agent for treatment of leukemia.  Based on these data, a Ph1b trial in AML has been initiated at multiple sites in the US.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): AML, Cell cycle, Drug sensitivity, Xenotransplantation

By continuing to browse or by clicking “Accept Terms & all Cookies”, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies