Ellen Yu-Hsi Lin

Sanofi | SHANTHA

Tumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition in...

Tumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition in...

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). We previously identified and characterized a competitive, small molecule phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX), and its lipophilic bis-ester pr...

Metabolically labile prodrugs can experience stark differences in catabolism incurred by the chosen route of administration. This is especially true for phosph(on)ate prodrugs, in which successive promoiety removal transforms a lipophilic molecule into increasingly polar compounds. We previously described a phosphonate inhibitor of enolase (HEX) an...

Genomic deletion of tumor suppressor genes (TSG) often encompasses neighboring genes which may be members of multi-gene families encoding cell essential functions. These genomic events create targetable cancer-specific vulnerabilities, termed “collateral lethality” as illustrated by homozygous deletion of the glycolytic gene ENO1 , which sensitizes...

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phos-phonate (HEX) (5), and...

Purpose: Advanced stage gastrointestinal cancers represent a high unmet need requiring new effective therapies. We investigated the anti-tumor activity of a novel T-cell engaging antibody (B7-H6/CD3 ITE) targeting B7-H6, a tumor-associated antigen that is expressed in gastrointestinal tumors. Experimental design: Membrane proteomics and immunohi...

Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their demise. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit...

Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anem...

Homozygous deletion of methylthioadenosine phosphorylase ( MTAP ) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP -deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which s...

Background Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates and must be replenished (anaplerosis), mainly from pyruvate and glutamine. We recently...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates by oxidation of anaplerotic substrates, such as glucose-derived pyruvate and glutamine20 derived g...

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. H...

Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their demise. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit...

Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are being investigated for obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a key do...

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on condition...

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on condition...

Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung...

In Brief The co-deletion of MTAP in the CDKN2A locus is a frequent event in diverse cancers including glioblastoma. Recent publications report that significant accumulations of the MTAP substrate, methylthioadenosine (MTA), can sensitize MTAP -deleted cancer cells to novel inhibitors of PRMT5 and MAT2A for targeted therapy against tumors with this...

We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a racemic-diastereomeric mixture. However, co-crystal structures with Enolase 2 (ENO2) have consistently...

We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a racemic-diastereomeric mixture. However, co-crystal structures with Enolase 2 (ENO2) have consistently...

Epigenetic modifiers have emerged as important regulators of tumor progression. We identified histone methyltransferase KMT2D as a potent tumor-suppressor through an in vivo epigenome-focused pooled RNAi screen in melanoma. KMT2D harbors frequent somatic point mutations in multiple tumor types. How these events contribute to tumorigenesis and wheth...

In the version of this article originally published, information regarding several funding sources was omitted from the Acknowledgements section. The following sentences should have been included: "This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program, the UT Lung S...

Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF ch...

Large-scale genomic profiling efforts, such as The Cancer Genome Atlas (TCGA) have painted an unprecedentedly detailed picture of the genetic alterations that underlie carcinogenesis, yet the key challenge remains as to how to turn this information into actionable therapies. Genomic deletions are a frequent event in diverse cancers, which inactivat...

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of t...

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We recently demonstrated that SF2312, a natural product phosphonate antibiotic, is a potent inhibitor of the glycolytic enzyme Enolase with potential utility for the collateral lethality-based treatment of Enolase-deficient glioblastoma (GBM). However, phosphonates...

Main Text: (Cancer Cell 32, 42–56; July 10, 2017) In the originally published version of this paper's Supplemental Information, incorrect headers were used for the gene signatures listed in Table S1. Specifically, the headers of the Proneural and the Mesenchymal gene signatures were swapped. To provide clarity, the authors are supplying a revised T...

Glioblastoma expression subtypes have been previously been associated with genomic abnormalities, treatment response, and differences in tumor microenvironment. We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural,...

Glycolysis inhibition is an active area of investigation for the treatment of cancer. However, few compounds have progressed beyond the cell culture stage. We have recently demonstrated that genomic passenger deletion of the glycolytic enzyme Enolase 1 (ENO1) leaves gliomas harboring such deletions solely reliant on ENO2, rendering them exquisitely...

We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In...

Inhibition of glycolysis is of great potential for the treatment of cancer. However, inhibitors of glycolytic enzymes with favorable pharmacological profiles have not been forthcoming. Due to the nature of their active sites, most high-affinity transition-state analogue inhibitors of glycolysis enzymes are highly polar with poor cell permeability....

Effect of Hypoxia on sensitivity to ENOblock and SF2312. D423 ENO1-deleted (red diamonds), D423 ENO1-rescued (blue squares) and LN319 ENO1-WT (grey circles) glioma cells were treated with indicated ENOblock doses (Panel a and b) or SF2312 (Panel c and d) and incubated either at 21% O2 indicated as Normoxia or 0.1% O2 indicated as Hypoxia for 3 days...

Purity analysis of recombinant ENO1 and ENO2. Panel a shows purity of recombinant ENO1 and ENO2 proteins by Ponceau staining and Coomasie staining. Panel b shows uncropped western blots from Fig 2 (Red rectangle indicates the blots used in Fig 2 for recombinant ENO1 and ENO2 proteins blotted with their respective antibodies (ENO1 antibody, 1:1000,...

Despite being crucial for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme enolase 2 (ENO2) for the treatment of cancers with deletion of ENO1 (encoding enolase 1), we modeled the synthetic tool compound inhibitor phosphonoacetohydroxa...

We leveraged IDH wild type glioblastomas and derivative neurospheres to define tumor-intrinsic transcription phenotypes. Transcriptomic multiplicity correlated with increased intratumoral heterogeneity and tumor microenvironment presence. In silico cell sorting demonstrated that M2 macrophages/microglia are the most frequent type of immune cells in...

Large scale genomic characterization efforts such as TCGA have painted an unprecedentedly detailed picture of the genetic alterations that underlie tumorigenesis. Yet, the majority of genetic alterations are passenger rather than driver events and are considered unactionable. We have previously proposed that passenger or collateral deletions could...

GBM remains one of the most difficult cancers to treat. Despite surgery, radiation and chemotherapy, tumors invariably recur. There is a strong correlation between extend of resection and subsequent time to recurrence and ultimate patient survival. A key challenge for the neurosurgeon is to minimize removal normal brain tissue whilst being as aggre...

Recent studies suggest that JAK2 serves as a novel therapeutic target in Bcr-Abl+ chronic myelogenous leukemia (CML). We have reported the existence of an HSP90- associated high molecular weight network complex (HMWNC) that is composed of HSP90 client proteins BCR-ABL, JAK2, and STAT3 in wild type Bcr-Abl+ leukemic cells. Here we showed that the HS...

Glycolysis inhibition is an active area of investigation in cancer. However, few compounds have progressed beyond the cell culture stage. We have recently demonstrated that genomic passenger deletion of the glycolytic enzyme Enolase 1 (ENO1) leaves gliomas harboring such deletions with less than 10% of normal enzymatic activity, rendering them exqu...

Glycolysis inhibition is an active area of investigation in cancer. However, few compounds have progressed beyond the cell culture stage. We have recently demonstrated that genomic passenger deletion of the glycolytic enzyme Enolase 1 (ENO1) leaves gliomas harboring such deletions with less than 10% of normal enzymatic activity, rendering them exqu...

Despite being critical for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme Enolase 2 for the treatment of cancers with deletion of Enolase 1, we modeled the tool compound inhibitor, Phosphonoacetohydroxamate (PhAH) into the active sit...

Glycolysis inhibition is an active area of investigation in cancer. However, few compounds have progressed beyond the cell culture stage. We have recently demonstrated that genomic passenger deletion of the glycolytic enzyme Enolase 1 (ENO1) leaves gliomas harboring such deletions with less than 10% of normal enzymatic activity, rendering them exqu...

GBM have been classified into four transcriptional subtypes, termed proneural, neural, classical, and mesenchymal, which are characterized by distinct genomic properties but reports on how transcriptional classification relates to clinical outcome have been conflicting. Methods for classification of new GBMs according to these subtypes have shown p...

Blood Cancer Journal is a peer-reviewed, open access online journal publishing pre-clinical and clinical work in the field of hematology with ramifications into translational biology research down to new therapies

4412 Chronic myeloid leukemia (CML) is a hematological disease caused by the fusion protein Bcr-Abl tyrosine kinase. Development of the tyrosine kinase inhibitor Imatinib Mesylate (IM) has significantly improved the long-term survival of early stage CML patients. However, occurrence of drug resistance, permanence of residual disease and recurrence...