Publications by authors named "Dean W Felsher"

140 Publications

Twist1 is required for the development of UVB-induced squamous cell carcinoma.

Mol Carcinog 2021 May 13;60(5):342-353. Epub 2021 Mar 13.

Division of Pharmacology and Toxicology, College of Pharmacy and the Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, Texas, USA.

The transcription factor Twist1 has been reported to be essential for the formation and invasiveness of chemically induced tumors in mouse skin. However, the impact of keratinocyte-specific Twist1 deletion on skin carcinogenesis caused by UVB radiation has not been reported. Deletion of Twist1 in basal keratinocytes of mouse epidermis using K5.Cre × Twist1 mice led to significantly reduced UVB-induced epidermal hyperproliferation. In addition, keratinocyte-specific deletion of Twist1 significantly suppressed UVB-induced skin carcinogenesis. Further analyses revealed that deletion of Twist1 in cultured keratinocytes or mouse epidermis in vivo led to keratinocyte differentiation. In this regard, deletion of Twist1 in epidermal keratinocytes showed significant induction of early and late differentiation markers, including TG1, K1, OVOL1, loricrin, and filaggrin. Similar results were obtained with topical application of harmine, a Harmala alkaloid that leads to degradation of Twist1. In contrast, overexpression of Twist1 in cultured keratinocytes suppressed calcium-induced differentiation. Further analyses using both K5.Cre × Twist1 mice and an inducible system where Twist1 was deleted in bulge region keratinocytes showed loss of expression of hair follicle stem/progenitor markers, including CD34, Lrig1, Lgr5, and Lgr6. These data support the conclusion that Twist1 has a direct role in maintaining the balance between proliferation and differentiation of keratinocytes and keratinocyte stem/progenitor populations. Collectively, these results demonstrate a critical role for Twist1 early in the process of UVB skin carcinogenesis, and that Twist1 may be a novel target for the prevention of cutaneous squamous cell carcinoma.
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http://dx.doi.org/10.1002/mc.23296DOI Listing
May 2021

Smart Self-Assembly Amphiphilic Cyclopeptide-Dye for Near-Infrared Window-II Imaging.

Adv Mater 2021 Apr 12;33(16):e2006902. Epub 2021 Mar 12.

Molecular Imaging Program at Stanford (MIPS), Bio-X Program, and Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA, 94305-5344, USA.

Development of novel nanomaterials for disease theranostics represents an important direction in chemistry and precision medicine. Fluorescent molecular probes in the second near-infrared window (NIR-II, 1000-1700 nm) show high promise because of their exceptional high detection sensitivity, resolution, and deep imaging depth. Here, a sharp pH-sensitive self-assembling cyclopeptide-dye, SIMM1000, as a smart nanoprobe for NIR-II imaging of diseases in living animals, is reported. This small molecule assembled nanoprobe exhibits smart properties by responding to a sharp decrease of pH in the tumor microenvironment (pH 7.0 to 6.8), aggregating from small nanoprobe (80 nm at pH 7.0) into large nanoparticles (>500 nm at pH 6.8) with ≈20-30 times enhanced fluorescence compared with the non-self-assembled CH-4T. It yields micrometer-scale resolution in blood vessel imaging and high contrast and resolution in bone and tumor imaging in mice. Because of its self-aggregation in acidic tumor microenvironments in situ, SIMM1000 exhibits high tumor accumulation and extremely long tumor retention (>19 days), while being excretable from normal tissues and safe. This smart self-assembling small molecule strategy can shift the paradigm of designing new nanomaterials for molecular imaging and drug development.
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http://dx.doi.org/10.1002/adma.202006902DOI Listing
April 2021

A mathematical model of tumor regression and recurrence after therapeutic oncogene inactivation.

Sci Rep 2021 Jan 14;11(1):1341. Epub 2021 Jan 14.

Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.

The targeted inactivation of individual oncogenes can elicit regression of cancers through a phenomenon called oncogene addiction. Oncogene addiction is mediated by cell-autonomous and immune-dependent mechanisms. Therapeutic resistance to oncogene inactivation leads to recurrence but can be counteracted by immune surveillance. Predicting the timing of resistance will provide valuable insights in developing effective cancer treatments. To provide a quantitative understanding of cancer response to oncogene inactivation, we developed a new 3-compartment mathematical model of oncogene-driven tumor growth, regression and recurrence, and validated the model using a MYC-driven transgenic mouse model of T-cell acute lymphoblastic leukemia. Our mathematical model uses imaging-based measurements of tumor burden to predict the relative number of drug-sensitive and drug-resistant cancer cells in MYC-dependent states. We show natural killer (NK) cell adoptive therapy can delay cancer recurrence by reducing the net-growth rate of drug-resistant cells. Our studies provide a novel way to evaluate combination therapy for personalized cancer treatment.
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http://dx.doi.org/10.1038/s41598-020-78947-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809285PMC
January 2021

Genomic analysis of Vascular Invasion in Hepatocellular Carcinoma (HCC) Reveals Molecular Drivers and Predictive Biomarkers.

Hepatology 2020 Nov 3. Epub 2020 Nov 3.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, CA, United States.

Vascular invasion is a critical risk factor for hepatocellular carcinoma (HCC) recurrence and poor survival. The molecular drivers of vascular invasion in HCC are largely unknown. Deciphering the molecular landscape of invasive HCC will help identify novel therapeutic targets and noninvasive biomarkers. To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with vascular invasion using the multi-platform cancer genome atlas (TCGA) data (n=373). In the TCGA liver hepatocellular carcinoma (LIHC) cohort, macrovascular invasion was present in 5% (n=17) of tumors and microvascular invasion in 25% (n=94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA and proteomic changes in vascular invasion. We performed comparative proteomic analyses of invasive human HCC and MYC driven murine HCC and identified fibronectin to be proteomic biomarker of invasive HCC (mouse Fn1 p= 1.7 X 10 ; human FN1 p=1.5 X 10 ) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n=153; p<0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n=35, mean=307.7 μg/ml, SEM=35.9) when compared to cirrhosis (n=10, mean=41.8 μg/ml, SEM=13.3; p<0.0001). CONCLUSION: Our study evaluates the molecular landscape of tumors with vascular invasion, identifying distinct transcriptional, epigenetic and proteomic changes driven by the MYC oncogene. We show that MYC upregulates fibronectin expression which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising non-invasive proteomic biomarker of vascular invasion in HCC.
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http://dx.doi.org/10.1002/hep.31614DOI Listing
November 2020

Mitochondrial copper depletion suppresses triple-negative breast cancer in mice.

Nat Biotechnol 2021 03 19;39(3):357-367. Epub 2020 Oct 19.

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.

Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.
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http://dx.doi.org/10.1038/s41587-020-0707-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956242PMC
March 2021

MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC.

Mol Ther Nucleic Acids 2020 Sep 10;21:850-859. Epub 2020 Jul 10.

Division of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

The MYC oncogene is dysregulated in most human cancers and hence is an attractive target for cancer therapy. We and others have shown experimentally in conditional transgenic mouse models that suppression of the MYC oncogene is sufficient to induce rapid and sustained tumor regression, a phenomenon known as oncogene addiction. However, it is unclear whether a therapy that targets the MYC oncogene could similarly elicit oncogene addiction. In this study, we report that using antisense oligonucleotides (ASOs) to target and reduce the expression of MYC impedes tumor progression and phenotypically elicits oncogene addiction in transgenic mouse models of MYC-driven primary hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Quantitative image analysis of MRI was used to demonstrate the inhibition of HCC and RCC progression. After 4 weeks of drug treatment, tumors had regressed histologically. ASOs depleted MYC mRNA and protein expression in primary tumors in vivo, as demonstrated by real-time PCR and immunohistochemistry. Treatment with MYC ASO in vivo, but not with a control ASO, decreased proliferation, induced apoptosis, increased senescence, and remodeled the tumor microenvironment by recruitment of CD4 T cells. Importantly, although MYC ASO reduced both mouse Myc and transgenic human MYC, the ASO was not associated with significant toxicity. Lastly, we demonstrate that MYC ASO inhibits the growth of human liver cancer xenografts in vivo. Our results illustrate that targeting MYC expression in vivo using ASO can suppress tumorigenesis by phenotypically eliciting both tumor-intrinsic and microenvironment hallmarks of oncogene addiction. Hence, MYC ASO therapy is a promising strategy to treat MYC-driven human cancers.
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http://dx.doi.org/10.1016/j.omtn.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452286PMC
September 2020

The Myc and Ras Partnership in Cancer: Indistinguishable Alliance or Contextual Relationship?

Cancer Res 2020 09 30;80(18):3799-3802. Epub 2020 Jul 30.

Division of Oncology, Department of Medicine, Stanford University, Stanford, California.

Myc and Ras are two of the most commonly activated oncogenes in tumorigenesis. Together and independently they regulate many cancer hallmarks including proliferation, apoptosis, and self-renewal. Recently, they were shown to cooperate to regulate host tumor microenvironment programs including host immune responses. But, is their partnership always cooperative or do they have distinguishable functions? Here, we provide one perspective that Myc and Ras cooperation depends on the genetic evolution of a particular cancer. This in turn, dictates when they cooperate via overlapping and identifiably distinct cellular- and host immune-dependent mechanisms that are cancer type specific.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501217PMC
September 2020

MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies.

Nat Commun 2020 06 5;11(1):2860. Epub 2020 Jun 5.

Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA.

The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYC mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYC T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.
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http://dx.doi.org/10.1038/s41467-020-16447-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275060PMC
June 2020

The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them.

Cancer Epidemiol Biomarkers Prev 2020 10 9;29(10):1887-1903. Epub 2020 Mar 9.

Expansion Therapeutics Inc, San Diego, California.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards and We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483401PMC
October 2020

and cooperate to drive metastasis by eliciting crosstalk between cancer and innate immunity.

Elife 2020 01 14;9. Epub 2020 Jan 14.

Division of Oncology, Department of Medicine, Stanford University, Stanford, United States.

Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of and enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. and cooperate and their sustained expression is required to elicit a transcriptional program associated with the activation of innate immunity, through secretion of a cytokinome that elicits recruitment and polarization of tumor associated macrophages (TAMs). Systemic treatment with Ccl2 and Il13 induced -HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated /-HCC metastasis. Further, in 33 human cancers (n = 9502) and predict poor survival (p=4.3×10), CCL2/IL13 expression (p<10) and TAM infiltration (p<10). Finally, in the plasma of patients with HCC (n = 25) but not cirrhosis (n = 10), CCL2 and IL13 were increased and IL13 predicted invasive tumors. Therefore, and generally appear to cooperate in human cancer to elicit a cytokinome that enables metastasis through crosstalk between cancer and immune microenvironment.
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http://dx.doi.org/10.7554/eLife.50731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959993PMC
January 2020

Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index.

Sci Rep 2019 11 14;9(1):16775. Epub 2019 Nov 14.

Department of Computer Science, Stanford University, Stanford, CA, 94305, USA.

Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.
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http://dx.doi.org/10.1038/s41598-019-53290-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856101PMC
November 2019

The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth.

Cell Metab 2019 09 22;30(3):556-572.e5. Epub 2019 Aug 22.

Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis.
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http://dx.doi.org/10.1016/j.cmet.2019.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911354PMC
September 2019

Conditional Upregulation of IFN-α Alone Is Sufficient to Induce Systemic Lupus Erythematosus.

J Immunol 2019 08 19;203(4):835-843. Epub 2019 Jul 19.

Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142, Japan;

The cause of systemic lupus erythematosus (SLE) is unknown. IFN-α has been suggested as a causative agent of SLE; however, it was not proven, and to what extent and how IFN-α contributes to the disease is unknown. We studied the contribution of IFN-α to SLE by generating inducible IFN-α transgenic mice and directly show that conditional upregulation of IFN-α alone induces a typical manifestation of SLE in the mice not prone to autoimmunity, such as serum immune complex, autoantibody against dsDNA (anti-dsDNA Ab), and the organ manifestations classical to SLE, such as immune complex-deposited glomerulonephritis, classical splenic onion-skin lesion, alopecia, epidermal liquefaction, and positive lupus band test of the skin. In the spleen of mice, activated effector CD4 T cells, IFN-γ-producing CD8 T cells, B220CD86 cells, and CD11cCD86 cells were increased, and the T cells produced increased amounts of IL-4, IL-6, IL-17, and IFN-γ and decreased IL-2. In particular, activated CD3CD4CD8 double-negative T cells positive for TCRαβ, B220, CD1d-teteramer, PD-1, and Helios (that produced increased amounts of IFN-γ, IL-4, IL-17, and TNF-α) were significantly expanded. They infiltrated into kidney and induced de novo glomerulonephritis and alopecia when transferred into naive recipients. Thus, sole upregulation of IFN-α is sufficient to induce SLE, and the double-negative T cells expanded by IFN-α are directly responsible for the organ manifestations, such as lupus skin disease or nephritis.
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http://dx.doi.org/10.4049/jimmunol.1801617DOI Listing
August 2019

Regulates the Stemness Pathway via and to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells.

Cancer Res 2019 08 2;79(16):4015-4025. Epub 2019 Jul 2.

Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California.

Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T-cell leukemia, MYC, maintains self-renewal in Sca1 CSCs versus Sca-1 non-CSCs. MYC preferentially bound to the promoter and activated hypoxia-inducible factor-2α () in Sca-1 cells only. Furthermore, the reprogramming factors, and , facilitated MYC regulation of in Sca-1 versus Sca-1 cells. Reduced expression of inhibited the self-renewal of Sca-1 cells; this effect was blocked through suppression of ROS by N-acetyl cysteine or the knockdown of p53, , or . Similar results were seen in ABCG2 CSCs versus ABCG2 non-CSCs from primary human T-cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications. SIGNIFICANCE: These findings show that the stemness pathway maintains leukemic stem cells downstream of MYC in human and mouse T-cell leukemias. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4015/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701948PMC
August 2019

A Tale of Two Complications of Obesity: NASH and Hepatocellular Carcinoma.

Hepatology 2019 09 27;70(3):1056-1058. Epub 2019 May 27.

Division of Medical Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA.

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http://dx.doi.org/10.1002/hep.30649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717523PMC
September 2019

Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription.

Cell Chem Biol 2019 05 14;26(5):711-723.e14. Epub 2019 Mar 14.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.
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http://dx.doi.org/10.1016/j.chembiol.2019.02.009DOI Listing
May 2019

Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma.

J Immunother Cancer 2018 11 20;6(1):125. Epub 2018 Nov 20.

Division of Medical Oncology, Departments of Medicine and Pathology, Stanford University, CA, Stanford, USA.

Interleukin-12 (IL-12) is a promising candidate for cancer immunotherapy because of its ability to activate a number of host immune subsets that recognize and destroy cancer cells. We found that human hepatocellular carcinoma (HCC) patients with higher than median levels of IL-12 have significantly favorable clinical outcomes. Here, we report that a messenger RNA (mRNA) lipid nanoparticle delivering IL-12 (IL-12-LNP) slows down the progression of MYC oncogene-driven HCC. IL-12-LNP was well distributed within the HCC tumor and was not associated with significant animal toxicity. Treatment with IL-12-LNP significantly reduced liver tumor burden measured by dynamic magnetic resonance imaging (MRI), and increased survival of MYC-induced HCC transgenic mice in comparison to control mice. Importantly, IL-12-LNP exhibited no effect on transgenic MYC levels confirming that its therapeutic efficacy was not related to the downregulation of a driver oncogene. IL-12-LNP elicited marked infiltration of activated CD44 CD3 CD4 T helper cells into the tumor, and increased the production of Interferon γ (IFNγ). Collectively, our findings suggest that IL-12-LNP administration may be an effective immunotherapy against HCC.
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http://dx.doi.org/10.1186/s40425-018-0431-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247677PMC
November 2018

The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma.

Oncogene 2018 10 5;37(40):5435-5450. Epub 2018 Jun 5.

Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.

Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Here we investigated metabolic dependencies in a panel of ccRCC cell lines using nutrient depletion, functional RNAi screening and inhibitor treatment. We found that ccRCC cells are highly sensitive to the depletion of glutamine or cystine, two amino acids required for glutathione (GSH) synthesis. Moreover, silencing of enzymes of the GSH biosynthesis pathway or glutathione peroxidases, which depend on GSH for the removal of cellular hydroperoxides, selectively reduced viability of ccRCC cells but did not affect the growth of non-malignant renal epithelial cells. Inhibition of GSH synthesis triggered ferroptosis, an iron-dependent form of cell death associated with enhanced lipid peroxidation. VHL is a major tumour suppressor in ccRCC and loss of VHL leads to stabilisation of hypoxia inducible factors HIF-1α and HIF-2α. Restoration of functional VHL via exogenous expression of pVHL reverted ccRCC cells to an oxidative metabolism and rendered them insensitive to the induction of ferroptosis. VHL reconstituted cells also exhibited reduced lipid storage and higher expression of genes associated with oxidiative phosphorylation and fatty acid metabolism. Importantly, inhibition of β-oxidation or mitochondrial ATP-synthesis restored ferroptosis sensitivity in VHL reconstituted cells. We also found that inhibition of GSH synthesis blocked tumour growth in a MYC-dependent mouse model of renal cancer. Together, our data suggest that reduced fatty acid metabolism due to inhibition of β-oxidation renders renal cancer cells highly dependent on the GSH/GPX pathway to prevent lipid peroxidation and ferroptotic cell death.
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http://dx.doi.org/10.1038/s41388-018-0315-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173300PMC
October 2018

The MYC oncogene is a global regulator of the immune response.

Blood 2018 05 7;131(18):2007-2015. Epub 2018 Mar 7.

Division of Oncology, Department of Medicine, and.

The MYC proto-oncogene is a gene product that coordinates the transcriptional regulation of a multitude of genes that are essential to cellular programs required for normal as well as neoplastic cellular growth and proliferation, including cell cycle, self-renewal, survival, cell growth, metabolism, protein and ribosomal biogenesis, and differentiation. Here, we propose that MYC regulates these programs in a manner that is coordinated with a global influence on the host immune response. MYC had been presumed to contribute to tumorigenesis through tumor cell-intrinsic influences. More recently, MYC expression in tumor cells has been shown to regulate the tumor microenvironment through effects on both innate and adaptive immune effector cells and immune regulatory cytokines. Then, MYC was shown to regulate the expression of the immune checkpoint gene products CD47 and programmed death-ligand 1. Similarly, other oncogenes, which are known to modulate MYC, have been shown to regulate immune checkpoints. Hence, MYC may generally prevent highly proliferative cells from eliciting an immune response. MYC-driven neoplastic cells have coopted this mechanism to bypass immune detection. Thus, MYC inactivation can restore the immune response against a tumor. MYC-induced tumors may be particularly sensitive to immuno-oncology therapeutic interventions.
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http://dx.doi.org/10.1182/blood-2017-11-742577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934797PMC
May 2018

Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC).

Oncotarget 2018 Jan 9;9(5):5517-5528. Epub 2017 Nov 9.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options. Genomic amplification and/or overexpression of the MYC oncogene is a common molecular event in HCC, thus making it an attractive target for drug therapy. Unfortunately, currently there are no direct drug therapies against MYC. As an alternative strategy, microRNAs regulated by MYC may be downstream targets for therapeutic blockade. MiR-17 family is a microRNA family transcriptionally regulated by MYC and it is commonly overexpressed in human HCCs. In this study, we performed systemic delivery of a novel lipid nanoparticle (LNP) encapsulating an anti-miR-17 oligonucleotide in a conditional transgenic mouse model of MYC driven HCC. Treatment with anti-miR-17 , but not with a control anti-miRNA, resulted in significant de-repression of direct targets of miR-17, robust apoptosis, decreased proliferation and led to delayed tumorigenesis in MYC-driven HCCs. Global gene expression profiling revealed engagement of miR-17 target genes and inhibition of key transcriptional programs of MYC, including cell cycle progression and proliferation. Hence, anti-miR-17 is an effective therapy for MYC-driven HCC.
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http://dx.doi.org/10.18632/oncotarget.22342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814155PMC
January 2018

DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt's lymphoma.

Oncotarget 2017 Sep 10;8(44):76898-76920. Epub 2017 Aug 10.

Augusta University, Department of Biochemistry and Molecular Biology, Augusta, GA 30912, USA.

Aberrant DNA methylation is a hallmark of cancer. However, our understanding of how tumor cell-specific DNA methylation patterns are established and maintained is limited. Here, we report that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt's lymphoma the oncogene causes overexpression of DNA methyltransferase (DNMT) 1 and 3B, which contributes to tumor maintenance. By utilizing a tetracycline-regulated transgene in a mouse T-ALL (EμSRα-tTA;tet-o-MYC) and human Burkitt's lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC-inactivation. Chromatin immunoprecipitation indicated that MYC binds to the and promoters, implicating a direct transcriptional regulation. Hence, shRNA-mediated knock-down of endogenous MYC in human T-ALL and Burkitt's lymphoma cell lines downregulated DNMT3B expression. Knock-down and pharmacologic inhibition of DNMT3B in T-ALL reduced cell proliferation associated with genome-wide changes in DNA methylation, indicating a tumor promoter function during tumor maintenance. We provide novel evidence that MYC directly deregulates the expression of both and maintenance DNMTs, showing that MYC controls DNA methylation in a genome-wide fashion. Our finding that a coordinated interplay between the components of the DNA methylating machinery contributes to MYC-driven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.
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http://dx.doi.org/10.18632/oncotarget.20176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652751PMC
September 2017

Administration of low-dose combination anti-CTLA4, anti-CD137, and anti-OX40 into murine tumor or proximal to the tumor draining lymph node induces systemic tumor regression.

Cancer Immunol Immunother 2018 01 13;67(1):47-60. Epub 2017 Sep 13.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

The delivery of immunomodulators directly into the tumor potentially harnesses the existing antigen, tumor-specific infiltrating lymphocytes, and antigen presenting cells. This can confer specificity and generate a potent systemic anti-tumor immune response with lower doses and less toxicity compared to systemic administration, in effect an in situ vaccine. Here, we test this concept using the novel combination of immunomodulators anti-CTLA4, -CD137, and -OX40. The triple combination administered intratumorally at low doses to one tumor of a dual tumor mouse model had dramatic local and systemic anti-tumor efficacy in lymphoma (A20) and solid tumor (MC38) models, consistent with an abscopal effect. The minimal effective dose was 10 μg each. The effect was dependent on CD8 T-cells. Intratumoral administration resulted in superior local and distant tumor control compared to systemic routes, supporting the in situ vaccine concept. In a single tumor A20 model, injection close to the tDLN resulted in similar efficacy as intratumoral and significantly better than targeting a non-tDLN, supporting the role of the tDLN as a viable immunotherapy target in addition to the tumor itself. Distribution studies confirmed expected concentration of antibodies in tumor and tDLN, in keeping with the anti-tumor results. Overall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration.
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http://dx.doi.org/10.1007/s00262-017-2059-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446289PMC
January 2018

MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma.

Nat Commun 2017 06 8;8:15770. Epub 2017 Jun 8.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.
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http://dx.doi.org/10.1038/ncomms15770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472759PMC
June 2017

Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma.

Proc Natl Acad Sci U S A 2017 04 11;114(17):4300-4305. Epub 2017 Apr 11.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;

KRAS gene mutation causes lung adenocarcinoma. KRAS activation has been associated with altered glucose and glutamine metabolism. Here, we show that KRAS activates lipogenesis, and this activation results in distinct proteomic and lipid signatures. By gene expression analysis, KRAS is shown to be associated with a lipogenesis gene signature and specific induction of fatty acid synthase (FASN). Through desorption electrospray ionization MS imaging (DESI-MSI), specific changes in lipogenesis and specific lipids are identified. By the nanoimmunoassay (NIA), KRAS is found to activate the protein ERK2, whereas ERK1 activation is found in non-KRAS-associated human lung tumors. The inhibition of FASN by cerulenin, a small molecule antibiotic, blocked cellular proliferation of KRAS-associated lung cancer cells. Hence, KRAS is associated with activation of ERK2, induction of FASN, and promotion of lipogenesis. FASN may be a unique target for KRAS-associated lung adenocarcinoma remediation.
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http://dx.doi.org/10.1073/pnas.1617709114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410819PMC
April 2017

MYC: Master Regulator of Immune Privilege.

Trends Immunol 2017 04 21;38(4):298-305. Epub 2017 Feb 21.

Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Cancers are often initiated by genetic events that activate proto-oncogenes or inactivate tumor-suppressor genes. These events are also crucial for sustained tumor cell proliferation and survival, a phenomenon described as oncogene addiction. In addition to this cell-intrinsic role, recent evidence indicates that oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many oncogenes or loss of tumor suppressors induces the expression of immune checkpoints that regulate the immune response, such as PD-L1. We discuss here how oncogenes, and in particular MYC, suppress immune surveillance, and how oncogene-targeted therapies may restore the immune response against tumors.
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http://dx.doi.org/10.1016/j.it.2017.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378645PMC
April 2017

KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study.

Leuk Res 2016 11 28;50:123-131. Epub 2016 Sep 28.

H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.

EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.
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http://dx.doi.org/10.1016/j.leukres.2016.09.012DOI Listing
November 2016

BIM-mediated apoptosis and oncogene addiction.

Aging (Albany NY) 2016 09;8(9):1834-1835

Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA.

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http://dx.doi.org/10.18632/aging.101072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076438PMC
September 2016

Affordable Cancer Medications Are Within Reach but We Need a Different Approach.

J Clin Oncol 2016 06 9;34(18):2194-5. Epub 2016 May 9.

Lancaster University, Lancaster, United Kingdom.

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http://dx.doi.org/10.1200/JCO.2016.67.2436DOI Listing
June 2016

BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia.

Oncotarget 2016 May;7(19):26926-34

Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA, United States of America.

Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.
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http://dx.doi.org/10.18632/oncotarget.8731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053622PMC
May 2016