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Richard G. Pestell, AO, MD, PhD, MBA, MB, BS, FRACP, FACP, FRCP (London), FRCP (Ireland), MAE

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Richard Pestell, AO, MD, PhD, MBA, MB, BS, FRACP, FACP, FRCP (Ireland), FRCP (London), MAE, is a clinician scientist, who currently serves as the President of the Pennsylvania Cancer and Regenerative Medicine Center, and Member of Wistar Institute Cancer Center (Associate), in Philadelphia, USA.

He was previously Executive Vice President Thomas Jefferson University, Philadelphia, USA (30,000 employees, $5.6B USD annual budget.

background

Dr. Pestell’s education was in medicine, cancer research and business. He received M.D. and Ph.D. degrees from Melbourne University, and his MBA from NYU, Stern School of Business. Dr. Pestell completed his M.B., BS at the University of Western Australia, and conducted clinical training in Internal Medicine, Oncology and Endocrinology. He was the Winthrop Fellow at Harvard Medical School and was Clinical Fellow at Massachusetts General Hospital.

He has received awards and elected memberships (~20) to academic societies for his research, clinical care, and impact on improving healthcare access. He was appointed as an Officer of the Order of Australia from Queen Elizabeth II (2019) for “distinguished service to medicine, and to medical education, as a researcher and physician in the fields of endocrinology and oncology”. https://en.wikipedia.org/wiki/Richard_Pestell.

Other Elected Memberships include Academia Europaea, the American Society for Clinical Investigation. Awards include the RD Wright Medallion, The Eric Susman Prize in Medicine, Doctor of Medical Sciences, Honoris Causa, University of Melbourne, Doctor Honoris Causa, University of Western Australia 

He previously and or currently served as a member of the Editorial Board of 14 journals, as a Reviewer of 18 funding agencies in 9 countries, and consults for domestic and international research organizations and governments including Hungary.

He has founded six biotechnology companies (LightSeed, Shenandoah, ioROC, StromaGenesis, ProstaGene, EcoGenome). He sold ProstaGene with a successful exit in 2018. His companies have been financed primarily through NIH funded research and private investors. 

He has been the Principal Investigator of >$86mMM USD in grants primarily from the NIH, raised ~$50MM USD from investors for biotechnology company development, published more than 700 works with >99,000 citations, H index 159 and is ranked by Google Scholar #1 in the world for his area of science (“cell cycle”). He holds multiple issued patents in cancer diagnostics and treatment. Of 484 publications published 1996-2023, 161 have been cited in in 677 patents (SciVal). He has authored 1 book, 52 book chapters and delivered 294 invited lectures and 236 meeting presentations.

His research has led to the current use of new therapies. Dr. Pestell identified key genetic targets for cancer, including cyclins and CCR5.

(1) His preclinical studies of cyclin D1 in breast cancer were cited as the basis for the clinical trials of CDK inhibitors, now approved by the FDA for treatment of cancer.

(2) His preclinical studies of CCR5 inhibitors are cited as the basis for the current clinical trials of CCR5 inhibitors for cancer (3).

(3). His discovery that nuclear receptors are acetylated, thereby governing diverse functions, provided important insights into hormone signaling and cancer.    

 

Contributions to Science

Prostate cancer: As prostate cancer onset and progression involves the mune system we developed a metastatic murine model that recapitulates human prostate cancer, both geneticaly and epigenetically, and metastasizes to bones and brain in the muse.. We demonstrated that in human prostate cancer cells the abundance of cyclin D1 is induced by growth factors and siRNA to cyclin D1 reduced ErbB2-mediated DNA synthesis in LNCaP cells (Cancer Research, 2007; 67(9):4364-4372)., that cyclin D1 restrains EMT and promotes stem cell expanding gene expression in the prostate. This may contribute to its strong prognostic value for poor outcome in biochemical-free recurrence in human prostate cancer (Cancer Research, 2014; Jan 15; 74(2):508-19).

Dach1 and Cancer. Dach1 was initially cloned as a gene governing eye development. Dr. Pestell has led in the field of Dach1 in tumorigenesis. Pestell was the first to show that Dach1 restrains tumor growth, that the abundance of Dach1 is reduced in human cancers and that Dach1 restrains stem cells through reprogramming an Oct/Nanog/EKLF pathway. He was the first to show Dach1 binds to non-canonical TF binding sites (c-Jun, Smad) and bind DNA directly to promote gene expression modules. He showed Dach1 is phosphorylated and acetylated and controls breast cancer epithelial cell growth and migration in vitro and in vivo.

Androgen and Nuclear receptor acetylation. Dr. Pestell was the first to show nuclear receptors including the androgen receptor, are acetylated, that acetylation regulates contact-independent growth, and that this event is rate-limiting in hormone signaling and that acetylation is a general mechanism conserved among diverse nuclear receptors regulating diverse biological processes. Dr. Pestell proved that a single residue acetylated in the nuclear receptor, converted a growth suppressor into a growth activator. There have been >19,300 publications on nuclear receptor acetylation since our original discovery.

Cancer Stem cells. The Pestell lab has defined the requirement for specific target genes in the formation of breast and prostate epithelial cancer stems cells using transgenic or inducible knockout mice (NFκB, p21CIP1, c-jun) and have defined distinct roles for cyclin D1 in polarity vs stem cell function. These transgenic animals have been shared widely with the research community.

Cyclin D1 non canonical functions governing gene expression. Dr. Pestell has been a pioneer in the understanding of cell-cycle control in cancer. He was the first to show that: 1) cyclins are direct transcriptional targets of oncogenic and tumor suppressor signals; 2) cyclin D1 expression is rate-limiting for oncogeneinduced breast tumor and colon growth in vivo; 3) cyclin D1 binds DNA to regulate gene expression and chromosomal instability; 4) cyclins interact with nuclear receptors and tumor suppressors; 5) cyclins regulate mitochondrial metabolism, cellular migration, the non-coding genome and its biogenesis.

 
 

Selected Publications

1. Ju X, Ertel A, Casimiro MC, Yu Z, Meng H, McCue PA, Walters R, Fortina P, Lisanti MP, Pestell RG Novel oncogene-induced metastatic prostate cancer cell lines define human prostate cancer progression signatures. Cancer Res. 2013 Jan 15;73(2):978-89. doi: 10.1158/0008-5472.CAN-12-2133. Epub 2012 Nov 30. PMCID: PMC3561759.

2. Ju, X. and Casimiro, M.C., Gormley, M., Meng, H., Jiao, X., Katiyar, S., Crosariol, M., Chen, K., Wang, M., Quong, A.A., Lisanti MP, Ertel A, Pestell RG. Identification of a cyclin D1 network in prostate cancer that antagonizes epithelial-mesenchymal restraint. Cancer Research. 2014 Jan 15; 74(2):508-19. PMCID: PMC3914674.

3. Casimiro, M.C., Ju, X., Gormley, M., Meng, H., Jiao, X., Katiyar, S., Crosariol, M., Chen, K., Wang, M., Quong, A.A., Lisanti MP, Ertel A, Pestell RG. Cyclin D1 promotes androgen-dependent DNA damage repair in prostate cancer cells. Cancer Research, 2016 Jan 15;76(2):329-38. PMCID:PMC4715975.

4. Ju X, Jiao X, Ertel A, Casimiro MC, Di Sante G, Deng S, Li Z, Di Rocco A, Zhan T, Hawkins A, Stoyanova T, Andò S, Fatatis A, Lisanti MP, Gomella LG, Languino LR, Pestell RG. v-Src oncogene induces Trop2 proteolytic cleavage. Cancer Res. 2016 Sep 15 PMID:27634768

5. Wu K, Katiyar S, Li A, Liu M, Ju X, Popov VM, Jiao X, Lisanti MP, Casola A, Pestell RG. Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin- 8.. Proc Natl Acad Sci USA. 2008 May 13;105(19):6924-9. PMCID: PMC2374551.

6. Zhou J, Wang C, Wang Z, Dampier W, Wu K, Casimiro MC, Chepelev I, Popov VM, Quong A, Tozeren A, Zhao K, Lisanti MP, Pestell RG. Attenuation of Forkhead signaling by the retinal determination factor DACH1. Proc Natl Acad Sci USA. 2010 Apr 13;107(15):6864-9. doi: 10.1073/pnas.1002746107. Epub 2010 Mar 29, PMCID: PMC2872468.

7. Chen K, Wu K, Wang L, Jiao X, Ju X, Li Z, Ertel A, Addya S, McCue P, Lisanti MP, Wang C, Davis RJ, Mardon G, Pestell RG. The endogenous Cell-Fate Factor Dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a CXCL Signaling Module. Cancer Research. 2015 2015 May 15;75(10):1992-2004. PMID:25769723.

8. Ozcan L, Ghorpade D, Cristina de Sozua J, Chen K, Bessler M, Bagloo M, Schrope B, Pestell RG, Tabas, I. Hepatocyte DACH1 is Increased in Obesity Via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. Cell Rep. 2016 May 26. un 7;15(10):2214-25 PMID:27239042

9. Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, Ogryzko V, Avantaggiati ML, Pestell RG. p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J Biol Chem. 2000 Jul 7;275(27):20853- 60, PMCID: Identifier absent.

10. Wang, C., Fu, M., Angeletti, R.H., Siconolfi-Baez, L., Reutens, A.T., Albanese, C., Lisanti, M.P., Katzenellenbogen, B.S., Kato, S., Hopp, T., Fuqua, S.A., Lopez, G.N., Kushner, P.J., and Pestell, R.G., Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity. J Biol Chem. 2001 May 25; 276(21): p. 18375-83, PMCID: Identifier absent.

11. Fu M, Wang C, Wang J, Zhang X, Sakamaki T, Yeung YG, Chang C, Hopp T, Fuqua SA, Jaffray E, Hay RT, Palvimo JJ, Jänne OA, Pestell RG. Androgen Receptor Acetylation Governs Transactivation and MEKK1-Induced Apoptosis Without Effecting In Vitro Sumoylation and transrepression Function. Mol Cell Biol. 2002 May;22(10):3373-88.

12. Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D, Zhang X, Albanese C, Balk S, Chang C, Fan S, Rosen E, Palvimo JJ, Jänne OA, Muratoglu S, Avantaggiati ML, Pestell RG. Acetylation of the androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol. 2003 Dec;23(23):8563-75, PMCID: PMC262657

13. Liu, M., Casimiro, M.C., Wang, C., Shirley, L.A., Jiao, X., Katiyar, S., Ju, X., Li, Z., Yu, Z., Zhou, J., Johnson, M., Fortina, P., Hyslop, T., Windle, J.J., and Pestell, R.G., p21CIP1 attenuates Ras- and c-Mycdependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proc Natl Acad Sci USA. 2009 Nov 10; 106(45): p. 19035-9. PMCID: PMC2776463.

14. Genander, M., Halford, M.M., Xu, N.J., Eriksson, M., Yu, Z., Qiu, Z., Martling, A., Greicius, G., Thakar, S., Catchpole, T., Chumley, M.J., Zdunek, S., Wang, C., Holm, T., Goff, S.P., Pettersson, S., Pestell, R.G., Henkemeyer, M., and Frisen, J., Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell. 2009 Nov 13; 139(4): p. 679-92, PMCID: PMC2786256.

15. Liu, M., Sakamaki, T., Casimiro, M., Willmarth, N., Quong, A., Ju, X., Ojeifo, J., Jiao, X., Yeow, W-S., Wang, C.,Katiyar, S., Shirley, L., Albanese, C., Joyce, D., Pestell, R.G. The canonical NF-κB pathway governs mammary tumorigenesis in transgenic mice via tumor stem cell expansion. Cancer Res. 2010 Dec 15;70(24):10464-10473.,k, PMCID: PMC3010731.

16. Jiao , X., Katiyar, S., Willmarth, N.E., Liu, M., Ma, X., Flomenberg, N., Lisanti, M.P., and Pestell, R.G., cJun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J Biol Chem. 2010 Mar 12; 285(11): p. 8218-26. PMCID: PMC2832973.

17. Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK 3rd, Siegel PM, Hung MC, Yarden Y, Horowitz JM, Muller WJ, Pestell RG. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol. 2000 Jan;20(2):672-83. PMCID: PMC85165.

18. Neumeister P, Pixley FJ, Xiong Y, Xie H, Wu K, Ashton A, Cammer M, Chan A, Symons M, Stanley ER, Pestell RG. Cyclin D1 governs adhesion and motility of macrophages. Mol Biol Cell. 2003 May;14(5):2005-15. Epub 2003 Feb 21. PMCID: PMC165093.

19. Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, Fu M, Leader JE, Quong A, Novikoff PM, Pestell RG. Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc Natl Acad Sci USA. 2006 Aug 1;103(31):11567-72. Epub 2006 Jul 24. PMCID: PMC1518800.

20. Casimiro MC, Crosariol M, Loro E, Ertel A, Yu Z, Dampier W, Saria E, Papanikolaou A, Li Z, Wang C, Fortina P, Addya A, Tozeren A, Knudsen ES, Arnold A, Pestell RG. ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. J Clin Invest. 2012 Mar 1;122(3):833-43. doi: 10.1172/JCI60256. Epub 2012 Feb 6. PMCID: PMC3287228.

21. Polepallia S, George SM, Sri Vidyaa RV, Rodrigues GS, Ramachandra L, Chandrashekar R, Nayak D, Rao PPN, Pestell RG, Rao M. Role of UHRF1 in Malignancy and its Function as a Therapeutic Target for Molecular Docking Towards the SRA Domain. Intl J of Biochem & Cell Bio 2019 Sept Vol 144 105558. Link to article available on Elsevier at https://authors.elsevier.com/c/1ZIFA4qcwYO5Yj