8:50 PM
Nov 29, 2018
 |  BC Innovations  |  Targets & Mechanisms

Revving up metabolism at ASH 2018

A dive into the ASH 2018 abstracts highlights cancer metabolism as a top focus

Cancer metabolism is a prominent theme at this year’s ASH meeting, with researchers broadening the tent from metabolic targets that drive hematologic malignancies to those that intersect with other hot topics, notably immuno-oncology and epigenetics.

BioCentury’s survey of 4,355 abstracts from this year’s meeting of the American Society of Hematology, which takes place Dec. 1- 4 in San Diego, identifies 77 new and emerging targets, documents new cell types being engineered to treat cancer and finds rising preclinical activity in multiple myeloma (MM).

Cancer metabolism emerges as a recurrent theme across modalities, indications and new and established targets.

At least 300 abstracts discuss cancer metabolism or targets associated with cancer metabolism, over 100 discuss cell therapies and over 300 cover epigenetics, and those three themes overlap in many of the abstracts.

Clinical headlines in cancer metabolism, both positive and negative, are likely behind much of the interest.

The last 18 months saw approvals for the first two drugs founded on the hypothesis that altered cellular metabolism contributes to tumorigenesis. Agios Pharmaceuticals Inc.’s Idhifa enasidenib and Tibsovo ivosidenib are both marketed for acute myelogenous leukemia (AML).

While Incyte Corp.’s Phase III failure in April of IDO1 antagonist epacadostat set back interest in that target, it piqued stakeholder appetite for finding and validating new targets in the immuno-metabolism space -- a division of the field that aims to modify immune cells to increase their ability to fight cancer (see “Raising Metabolism”).

This year’s abstracts contain at least 27 metabolic targets, over half of which play into immuno-metabolism (see “Table: Cancer Metabolism Targets at ASH”).

Table: Cancer metabolism targets at ASH

Cancer metabolism emerged as a dominant theme at the 2018 meeting of the American Society of Hematology (ASH). At least 27 targets with known metabolic function and links to cancer were discussed in at least one abstract. Source: ASH 2018 Abstracts; BCIQ: BioCentury Online Intelligence

PathwayTargetNumber of abstracts
Adenosine pathwayEcto-5'-nucleotidase (NT5E; CD73)10
Ectonucleoside triphosphate diphosphohydrolase 1 (CD39; ENTPD1)10
Adenosine receptors4
Adenosine A2B receptor (ADORA2B)1
Adenosine kinase1
Amino acid metabolismThymidylate synthetase (TYMS)1
Arginine pathwayArginase 1 (ARG1)8
Nitric oxide synthase3
Inducible nitric oxide synthase 2 (NOS2; iNOS)6
Fatty acid synthesisAcetyl-Coenzyme A carboxylase α (ACACA; ACC1)3
Fatty acid synthase (FASN; FAS)3
ATP citrate lyase (ACLY)2
Glutamine pathwayGlutaminase (GLS)3
Glutathione peroxidase (GPX)3
Glutathione peroxidase 1 (GPX1)3
GlycolysisSolute carrier family 2 facilitated glucose transporter member 1 (SLC2A; GLUT1)4
Glucose-6-phosphate dehydrogenase (G6PD)8
Prostacyclin receptor (PGI2; PTGIR)1
Krebs cycleIsocitrate dehydrogenase 1 (IDH1)102
Mitochondrial biogenesisCCAAT enhancer binding protein α (CEBPA)63
Peroxisome proliferation activated receptor γ coactivator 1-α (PGC-1α; PPARGC1A)5
Nucleic acid synthesisRibonucleotide reductase M2 (RRM2; R2)3
Tryptophan metabolismAryl hydrocarbon receptor (AHR)7
Indoleamine 2,3-dioxygenase (IDO; INDO)7
Indoleamine 2,3-dioxygenase 1 (IDO1)7
Kynurenine (KYN)4

IDH1 and IDH2, two metabolic targets inside cancer cells, are each represented in more than 100 abstracts; they, along with the metabolic enzyme CEBPA, feature in the top 100 most frequently mentioned targets at the conference.

Metabolic targets also feature in what BioCentury terms “emerging targets,” defined as those mentioned in no more than two abstracts in ASH 2017 and in four or more this year. Chief among these is PGC-1α, which is present in five abstracts this year, up from one last year (see “Adhesion Targets Emerge at ASH 2018”).

Abstracts on PGC-1α show inhibition of the target decreases mitochondrial respiration in cancer cells.

According to BioCentury’s BCIQ database, no companies are developing products targeting PGC-1α.

Cell therapies continue to gain ground in cancer abstracts at ASH 2018, appearing in 94 preclinical and 210 total abstracts, beating last year’s counts of 87 and 153, respectively (see “Figure: ASH 2018 Modalities”).

Figure: ASH 2018 modalities

New modalities in continue to be dominated by cell therapies at the 2018 American Society of Hematology (ASH) meeting, which account for 65% of new modality abstracts this year in cancer, compared with 60% last year. Clinical interest in cell therapies spiked, with a 76% rise over 2017 numbers, the bulk of which were in CAR T cells (see “ASH 2018 Cell Types”). Clinical interest in multispecific antibodies and nanoparticles also jumped up, with a similar, albeit more modest, trend in preclinical abstracts. In both classes, multispecific...

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