Arrigo De Benedetti, PhD

Arrigo De Benedetti, PhD

Professor

Major Research Interests: Prostate Cancer therapy based on the DNA Damage Response (DDR).

Standard therapy for advanced Prostate Cancer (PCa)consists of anti-androgens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome.  Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically.  We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR andChk1 activation, suggesting the existence of a TLK1>NEK1>ATR>Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen-independent (AI) colonies of LNCaP cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several CA cells in vitro (including androgen independent lines). Administration of THD or bicalutamide was not effective in inhibiting long-term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1-T141A mutant were suppressed with bicalutamide alone.  Collectively, these results strongly suggest that targeting the TLK1/NEK1 axis (with THD or J54) might be a novel therapy for PCa in combination with standard of care (ADT), likely also because of our novel discovery that Nek1 is a key mediator of the Hippo/YAP pathway.

Moreover, TLK1 is a key activator of a pathway regulated by MK5, which we are discovering is critical for PCa migration and metastasis. In addition to this project, we have another project dealing with the function of TLK1 in HDR based on its regulation of Rad54, and another studying cell motility/invasion/metastasis based on TLK1 interaction with MK5.

Major Research Interests: Mechanisms of DNA repair; Altered protein synthesis in solid tumors; Gene Expression; Gene Therapy.

a. Khalil, MDI, Singh, V, King, J, and De Benedetti, A.(2022) TLK1-mediated MK5-S354 phosphorylation drives prostate cancer cellmotility and may signify distinct pathologies. MOLONC 16: 2537-2557.https://doi.org/10.1002/1878-0261.13183.

b. Ghosh I, Khalil MI., Mirza R, King J., Olatunde D., andDe Benedetti A (2023) NEK1-Mediated Phosphorylation of YAP1 is key to ProstateCancer Progression. MDPI Biomedicines 11(3):734. https://doi.org/10.3390/biomedicines11030734

c. Singh, V., Bhoir, S., Chikhale, R.V., Hussain, J., Dwyer,D., Bryce, R.A., Kirubakaran, S., and De Benedetti, A (2020) Generation ofPhenothiazine with Potent anti-TLK1 Activity for Prostate Cancer Therapy.iScience. https://doi.org/10.1016/j.isci.2020.101474.

d. Singh, V.,Jaiswal, PK, Ghosh, I, Koul, HK, Yu, X. and De Benedetti, A (2019) Targetingthe TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of Androgenindependent prostate tumors. Int. J. Cancer 145: 1055-1067. doi:10.1002/ijc.32200.

Over the years wehave also published some important papers on the DDR.

a. Ghosh I., Kwon Y., Shabestari AB, Chikhale R, Chen J.,Wiese C., Sung P., and De Benedetti A. (2023) TLK1 mediated RAD54phosphorylation spatio-temporally regulates Homologous Recombination Repair.NAR (in press)

b. Awate, S, and De Benedetti, A (2016) TLK1B mediatedphosphorylation of Rad9 regulates its nuclear/cytoplasmic localization and cellcycle checkpoint. BMC Mol. Biol. 17:3.

c. Rath, A, Hromas, R, and De Benedetti, A (2014) Fidelityof End Joining in mammalian episomes and the impact of Metnase on jointprocessing. BMC-Mol Biol. 14:6.

d. Ronald, S, Awate, S, Rath, A, Carroll, J, Galiano, F,Dwyer, D, Kleiner, H, Mathis, JM, Vigod, S, and De Benedetti, A (2013)Phenothiazine inhibitors of TLKs affect DSB repair and DDR recovery andpotentiate tumor killing with radiomimetic therapy. Genes & Cancer 4:39–53.

ORCID:0000-0002-4198-8647

Lab website: https://www.lsuhs.edu/departments/school-of-graduate-studies/biochemistry-and-molecular-biology/research/de-benedetti-lab

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Ramsy Abdelghani, MD
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Jiri Adamec, PhD
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Suresh K. Alahari PhD
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Ashad Alam, MD, PhD
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Muralidharan Anbalagan, PhD
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Wayne L. Backes PhD
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Ambuga Badari, MD
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