A New Potential Target for Pancreatic Cancer Treatment: Rapid Screening Technique finds Gene Defending Tumors from DNA Damage @MD Anderson Cancer Center

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A New Potential Target for Pancreatic Cancer Treatment: Rapid Screening Technique finds Gene Defending Tumors from DNA Damage @MD Anderson Cancer Center

July 28, 2016 by 2012pharmaceutical

A New Potential Target for Pancreatic Cancer Treatment: Rapid Screening Technique finds Gene Defending Tumors from DNA Damage @M. D. Anderson Cancer Center

Reporter: Aviva Lev-Ari, PhD, RN

Novel gene-hunting method implicates new culprit in pancreatic cancer

Researchers develop rapid screening technique; find gene defends tumors from DNA damage

Date:: June 23, 2016
Source:: University of Texas M. D. Anderson Cancer Center
Summary:: Using an innovative approach to identify a cancer’s genetic vulnerabilities by more swiftly analyzing human tumors transplanted into mice, researchers have identified a new potential target for pancreatic cancer treatment.

WDR5 emerges as robust “hit”

WD repeat-containing protein 5 (WDR5), a core part of the COMPASS complex regulating chromatin function, was implicated in multiple screens. Recent research by others had shown WDR5 to be upregulated in prostate and bladder cancers and critical for cancer cell proliferation.

The team confirmed WDR5 was highly expressed in pancreatic cancer compared to normal pancreas tissue and then conducted a series of experiments which showed knocking down the gene impaired cell proliferation and tumor growth and greatly increased survival in mice.

Subsequent experiments showed WDR5 works in concert with Myc to protect pancreatic cancer from DNA damage. There is no known method for targeting either WDR5 or Myc separately, Carugo said, but the team thinks there might be ways to block their interaction.

While the team targeted epigenetic regulators, Carugo noted the technique can be used with other shRNA libraries aimed at different classes of genes.

This technology is being widely adopted by MD Anderson’s moon shot teams to identify genetic vulnerabilities and cancer targets specific to various disease subtypes.

Story Source:

The above post is reprinted from materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.

SOURCE

University of Texas M. D. Anderson Cancer Center. “Novel gene-hunting method implicates new culprit in pancreatic cancer: Researchers develop rapid screening technique; find gene defends tumors from DNA damage.” ScienceDaily. ScienceDaily, 23 June 2016. www.sciencedaily.com/releases/2016/06/160623115741.htm.

Alessandro Carugo et al. In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer. Cell Reports, June 2016 DOI:10.1016/j.celrep.2016.05.063

Cell Rep. 2016 Jun 28;16(1):133-47. doi: 10.1016/j.celrep.2016.05.063. Epub 2016 Jun 16.

In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer.

Carugo A¹, Genovese G², Seth S³, Nezi L², Rose JL², Bossi D⁴, Cicalese A⁴, Shah PK³, Viale A², Pettazzoni PF², Akdemir KC⁵, Bristow CA³,Robinson FS², Tepper J², Sanchez N², Gupta S⁶, Estecio MR⁷, Giuliani V³, Dellino GI⁸, Riva L⁹, Yao W², Di Francesco ME¹⁰, Green T², D’Alesio C⁴, Corti D², Kang Y¹¹, Jones P¹⁰, Wang H¹², Fleming JB¹¹, Maitra A⁶, Pelicci PG⁸, Chin L¹⁰, DePinho RA¹³, Lanfrancone L¹⁴, Heffernan TP¹⁵,Draetta GF¹⁶.

Author information

¹Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. Electronic address: acarugo@mdanderson.org.
²Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
³Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
⁵Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan 20139, Italy.
⁹Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy.
¹⁰Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
¹²Department of Pathology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. Electronic address: luisa.lanfrancone@ieo.eu.
¹⁵C-4 Therapeutics, Cambridge, MA 02142, USA. Electronic address: theffernan@c4therapeutics.com.
¹⁶Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: gdraetta@mdanderson.org.

Abstract

Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1-4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease.