Heidi Greulich

Heidi Greulich
Dana-Farber Cancer Institute | DFCI

PhD

About

146
Publications
22,623
Reads
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32,751
Citations
Citations since 2016
22 Research Items
13020 Citations
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201620172018201920202021202205001,0001,5002,000
Additional affiliations
January 2004 - present
Dana-Farber Cancer Institute
September 1995 - June 2000
Harvard University
Education
September 1989 - June 1995
The Rockefeller University
Field of study
  • Molecular Oncology
September 1985 - June 1989
Princeton University
Field of study
  • Molecular Biology

Publications

Publications (146)
Article
Full-text available
Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is...
Article
Velcrin compounds kill cancer cells expressing high levels of PDE3A and SLFN12 by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A-SLFN12 complex is not fully understood. We previously determined that SLFN12 is an RNase, that PDE3A binding upregulates SLFN12 RNase activity, and that SLFN12...
Article
Velcrins are small molecules that induce apoptosis of cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) by inducing PDE3A-SLFN12 complex formation. Recently, we found that SLFN12 is an RNase and PDE3A binding dramatically activates SLFN12 RNase activity, resulting in velcrin-mediated apoptosi...
Article
BAY 2666605, co-developed by the Broad Institute and Bayer Pharmaceuticals, is a selective and potent molecular glue, part of a family of small molecules recently baptized as ‘velcrins’, that induces complex formation between phosphodiesterase 3A (PDE3A) and SLFN12. BAY 2666605 has recently entered a First-in-Human study (NCT04809805) in patients w...
Article
Velcrin compounds are a class of small molecules that induce complex formation between PDE3A and SLFN12, killing cancer cells that express elevated levels of these two proteins by a mechanism independent of PDE3A enzymatic inhibition. Instead, PDE3A binding stimulates the RNase activity of SLFN12, resulting in cleavage of the specific SLFN12 substr...
Article
PDE3A-SLFN12 complex formation activates the SLFN12 RNase, but the biochemical details of RNase activation remain mysterious. In this issue of Cell Chemical Biology, Yan and colleagues report that two phosphoserines on SLFN12 are dephosphorylated in response to PDE3A binding, and this dephosphorylation is required for activation of the SLFN12 RNase...
Article
Full-text available
DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fu...
Conference Paper
We have identified a novel mechanism of selective cancer cell-killing, whereby small molecules such as DNMDP induce complex formation between phosphodiesterase 3A (PDE3A) and a poorly characterized protein, SLFN12, that leads to downstream cell death (de Waal et al., Nat Chem Biol 2016; Lewis et al., ACS Med Chem Letters, 2019; Wu et al., J Bio Che...
Conference Paper
Several targeted therapeutic options exist for non-small cell lung cancer (NSCLC) patients whose tumors harbor mutations of EGFR, including L858R, exon 19 deletions, and the acquired resistance mutation, T790M. However, there is no approved targeted therapy for patients with EGFR exon 20 insertions, highlighting an ongoing unmet medical need. Here,...
Conference Paper
PDE3A-SLFN12 complex formation is induced by a class of compounds, now called “velcrins”, exemplified by the small molecule, DNMDP. Cancer cells that express elevated levels of PDE3A and SLFN12 are sensitive to a velcrin-mediated cytotoxic response, which is independent of PDE3A inhibition. However, the details of complex formation have not yet bee...
Patent
The invention relates to substituted 4H-pyrrolo[3,2-c]pyridin-4-one compounds, a process for their production and uses thereof. It provides compounds that inhibit a mutant EGFR for the treatment of cancer.
Patent
The invention relates to substituted 4H-pyrrolo[3,2-c]pyridin-4-one compounds, processes for their production and uses thereof. It provides compounds that inhibit a mutant EGFR for the treatment of cancer.
Article
Full-text available
Anticancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth-inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM (profiling relative inhibition simultaneously in mixtures), a molecular barcoding me...
Article
Full-text available
Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) a...
Article
6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, potently and selectively inhibits phosphodiesterases 3A and 3B (PDE3A and PDE3B) and kills cancer cells by inducing PDE3A/B interactions with SFLN12. The structure-activity relationship (SAR) of DNMDP analogs was evaluated using a phenotypic viability assay, resul...
Preprint
Full-text available
Anti-cancer uses of non-oncology drugs have been found on occasion, but such discoveries have been serendipitous and rare. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. To accomplish this, we used PRISM, which involves drug treatment of molecularly barcoded...
Article
We have previously reported¹ our results with a small molecule called DNMDP which kills certain cancer cells by modulating the interaction of PDE3A and Schlafen 12 (SLFN12), a more recently discovered protein of unknown function. While DNMDP selectively inhibits PDE3, most PDE3 inhibitors have no cell killing effects and in fact rescue cancer cells...
Article
In a differential cytotoxicity screen, we identified a novel small molecule modulator of phosphodiesterase 3A (PDE3A) that kills cancer cells expressing elevated levels of PDE3A and SLFN12 (de Waal, Nat Chem Biol, 2016). Treatment with this cell-selective cytotoxic small molecule, DNMDP, induces complex formation between PDE3A and SLFN12, resulting...
Article
Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational met...
Article
High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolut...
Article
High cancer death rates indicate the need for new anti-cancer therapeutic agents. Approaches to discover new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identify phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds by phenotypic compound library screening and target deconvolution by pr...
Article
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Recent large sequencing and cancer dependency studies have accelerated the identification of candidate targets for precision medicine. However, the current drug development paradigm starting with target identification and validation can be slow and has thus far yielded a limited...
Article
Full-text available
Background: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradox...
Article
Full-text available
Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from...
Article
Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma who was treated with sorafenib demonstrated a near-complete clinical and radiographic remission for five years. Whole-genome sequencing and RNA sequencing on primary tumor and normal samples from thi...
Article
Full-text available
Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations i...
Article
Full-text available
Kinase domain mutations of the epidermal growth factor receptor (EGFR) are common oncogenic events in lung adenocarcinoma. Here we explore the dependency upon asymmetric dimerization of the kinase domain for activation of lung cancer-derived EGFR mutants. We show that while wild-type EGFR and the L858R mutant require dimerization for activation and...
Article
Full-text available
Despite the ongoing "war on cancer," cancer remains one of the major causes of human morbidity and mortality. A new paradigm of targeted therapies holds the most promise for the future, making identification of tumor-specific therapeutic targets of prime importance. ERBB2/HER2, best known for its role in breast cancer tumorigenesis, can be targeted...
Conference Paper
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Cervical cancer is a major public health problem worldwide. The etiological role of human papilloma virus (HPV) infections in cervical cancer is well established. However, HPV infection is insufficient to account for the development of cervical cancers because...
Article
Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of g...
Article
Full-text available
We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants we...
Article
Full-text available
Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis...
Article
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The ERBB2 receptor tyrosine kinase gene is frequently amplified and mutated in human cancer. However, mutations characterized to date have been located in the kinase domain of the receptor. Using publically-available sequencing datasets, we have found that extracellular...
Article
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Squamous cell lung carcinoma (lung SCC) is the second most common subtype of non-small cell lung cancer with, 40,000 new cases diagnosed every year in the United States. Unlike lung adenocarcinoma, few targetable genomic events are known drivers of lung SCC, and therefor...
Article
Squamous cell lung carcinoma (lung SCC)) is the second most common subtype of non-small cell lung cancer, with 40,000 new cases diagnosed every year in the United States. Unlike lung adenocarcinoma, few targetable genomic events are known drivers of lung SCC, and therefore, therapeutic options are limited for patients with this disease. As part of...
Data
WHSC1L1 histone methyltransferase activity domain is not likely to be specifically targeted for amplification at 8p11-12q. Heat map representation of SNP array based segmented copy number on chromosome arm 8p11-12q for 34 NSCLC samples (rows; ordered by amplification of a 170 kb chromosomal segment spanning WHSC1L1, LETM2 and FGFR1) having amplific...
Data
Categorization of 628 Primary Samples by 8p11 Amplification Status and Clinical Features. (XLS)
Data
Exclusion of WHSC1L1 functional domain among primary tumors harboring amplified FGFR1 and LETM2. Bar graph representation of unsegmented probe-level copy number values for amplicons in 3 primary tumor samples harboring break points within WHSC1L1. Estimated copy number values (y axis) are plotted for individual SNPs at 8p11-12 locus (x axis). Copy...
Data
FGFR1 tyrosine kinase activity is essential for NCI-H1581 anchorage independent growth. Inhibition of soft agar colony formation by the NCI-H1581 NSCLC cell line harboring FGFR1 amplification, in the presence of increasing concentrations of FGFR inhibitor PD173074, compared with HCC15 and NCI-H2170 cells without FGFR1 amplification, and NCI-H1703 c...
Data
FGFR1 instead of BRF2 is the more commonly amplified gene at 8p11. Copy-number data from chromosome 8p11-12 in 12 samples sorted by highest copy number on the top. The view is sorted by FGFR1 amplification (A) and BRF2 amplification (B). (A) Of the 12 samples with highest amplification at FGFR1 of log2 ratio above 2.5, only 4 samples amplify BRF2 a...
Data
List of NSCLC Samples Analyzed by SNP Array. (XLS)
Data
Elevated FGFR1 gene copy number in NSCLC cell lines. SNP array based segmented copy number on chromosome arm 8p11-12q for 18 NSCLC cell lines (rows; ordered by amplification) from telomere (left) to centromere (right). The color scale ranges from blue (deletion) to red (amplification) with estimated copy numbers shown. (TIF)
Data
Activation of FGFR1 substrate FRS2 in NCI-H1581 cells. Western blot analysis of FGFR1 in five different 8p11-12 amplified cells (Colo699, Calu3, NCI-H2077, NCIH1581, NCI-H520 and NCIH1703) indicated by red horizontal bar below and in three NSCLC cell lines harboring deletion of the region (NCI-H1781, NCI-H1563 and HCC15) indicated by blue horizonta...
Data
FGFR1 tyrosine kinase activity is essential in proliferation of NCI-H1581 cells. Treatment with the indicated concentrations of irreversible FGFR inhibitor FIIN-1 inhibited survival of NCI-H1581 cells, but not of NCI-H2170 cells, as determined by WST assay performed after 4 days treatment. IC50s are indicated. (TIF)
Data
Amplicons at 8p11-12 overlapping WHSC1L1, LETM2 and FGFR1. (XLS)
Article
Full-text available
Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma. Using SNP array analysis, we found that a region of chromosome segmen...
Article
Full-text available
Unlabelled: While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung...
Article
Full-text available
Despite significant progress in the molecular understanding of medulloblastoma, stratification of risk in patients remains a challenge. Focus has shifted from clinical parameters to molecular markers, such as expression of specific genes and selected genomic abnormalities, to improve accuracy of treatment outcome prediction. Here, we show how integ...
Article
Fibroblast growth factor receptors (FGFRs) play diverse roles in the control of cell proliferation, cell differentiation, angiogenesis and development. Activating the mutations of FGFRs in the germline has long been known to cause a variety of skeletal developmental disorders, but it is only recently that a similar spectrum of somatic FGFR mutation...
Article
Full-text available
Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large...
Article
Full-text available
Standard cytotoxic chemotherapy is effective for some cancers, but for many others, available treatments offer only a limited survival benefit. Lung adenocarcinoma is one such cancer, responsible for approximately half of lung cancer deaths each year. Development of targeted therapies is thought to hold the most promise for successfully treating th...
Article
Full-text available
Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samp...