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Naomi Pode Shakked, Student M.D-Ph.D

Naomi Pode Shakked

Student MD-PhD

Telephone: +972-3-5308134

Biography:

I'm a student in the MD-PhD program of the Sackler faculty of medicine, Tel Aviv University.

I have finished my PhD studies at the Pediatric Stem Cell Research Institute, Sheba Medical Center under the supervision of prof. Benjamin Dekel and am currently at the last year of my clinical studies toward an MD degree.

Research topic

Isolation of malignant renal stem cells for targeted therapy of Wilms' tumor

Main objective :It is becoming clear that many, if not most, malignancies arise from a population of cells that exclusively maintain the ability to self-renew and sustain the tumor via the expression of tumor-progenitor genes. These cancer stem cells'' or "tumor initiating cells" are often biologically distinct from the differentiated cancer cells that comprise most of the tumor bulk. Since cancer stem cells are believed to be primarily responsible for tumor initiation as well as resistance to chemo- and radiotherapy, their persistence after such therapies may account for relapsing disease. Hence, their therapeutic targeting may be essential to ensure complete tumor eradication.

Wilms' tumor (WT), a common childhood malignancy, is suggested to arise from a kidney precursor cell that undergoes partial differentiation and as such is an attractive model to study renal stem cells leading to cancer initiation.

The overall goal of this project is to identify and characterize the Wilms' tumor stem cells (WSC, self-renewing, multi-potent, and highly malignant) and to translate these findings to possible targeted therapy against such cells.

Recently using several methods we were able to identify and characterize the Wilms' tumor stem cells. These cells express high levels of stemness markers and account for a small percentage of the tumor cell population (1-10%). The identification of the Wilms' tumor stem cells highlighted putative therapeutic targets in WT, such as the NCAM molecule. Using a humanized NCAM antibody drug conjugate (ADC) we were able to target NCAM+ Wilms' tumor cells. In vitro targeting of NCAM+ cells by ADC depleted WT cultures from their "stemness" properties, while in vivo experiments showed robust results of WT eradication/growth attenuation in multiple Xn models.

The use of such antibodies may serve as a targeted therapy in children with Wilms' tumor, and may possibly carry significance in the treatment of additional pediatric solid tumors. These results can lead the way to focused treatment options against pediatrics cancer, which will eliminate the tumor and also prevent the significant adverse effects of current systemic treatments.

Publications

Dekel B, Metsuyanim S, Goldstein N, Pode Shakked N, Kovalsky Y, Anikster Y. Schimke immuno-osseous dysplasia: expression of SMARCAL1 in blood and kidney provides novel insight into disease phenotype.
Pediatric Research, 2008;63(4):398-403. (Included in Editor's Focus).

Metsuyanim S, Pode Shakked N, Schmidt KO, Blumental D, Keshet GI, Dekel B. Accumulation of malignant renal stem cells is associated with epigenetic changes in normal renal-progenitor genes.

Stem Cells, 2008 Jul;26(7):1808-17.

Pode-Shakked N, Metsuyanim S, Rom-Gross E, Mor Y, Fridman E, Goldstein I, Amariglio N, Rechavi G, Keshet G, Dekel B. Developmental tumourigenesis: NCAM as a putative marker for the malignant renal stem/progenitor cell population.

J Cell Mol Med., 2009 Aug;13(8B):1792-808.

Metsuyanim S, Harari-Steinberg O, Buzhor E, Omer D, Pode Shakked N, Ben-Hur H, Halperin R, Schneider D, Dekel B. Expression of Stem Cell Markers in the Human Fetal Kidney.

Plos One, 2009 Aug 21;4(8):e6709.

Werth M, Walentin K, Aue A, Schönheit J, Wuebken A, Pode-Shakked N, Vilianovitch L, Erdmann B, Dekel B, Bader M, Barasch J, Rosenbauer F, Luft FC, Schmidt-Ott KM. The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex.

Development, 2010 Nov;137(22):3835-45.

Pode Shakked N, Harari-Steinberg O, Haberman Y, Rom-Gross E, Zangi L, Bahar S, Omer D, Metsuyanim S, Buzhor E, Ronald S Goldstein, Michal Mark-Danieli, Dekel B. Resistance or sensitivity of Wilms' tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target.
Oncogene, 2011 Apr 7;30(14):1664-80. Epub 2011 Jan 17

Pode-Shakked N, Dekel B. Pediatr Nephrol. Wilms tumor-a renal stem cell malignancy?

Pediatric Nephrology 2011 Sep;26(9):1535-43. Epub 2011 Apr 16.

Vivante A, Lotan D, Pode-Shakked N, Landau D, Svec P, Nampoothiri S, Verma I, Abu-Libdeh A, Bockenhauer D, Dekel B, Anikster Y. Familial Autosomal Recessive Renal Tubular Acidosis: Importance of Early Diagnosis.

Nephron Physiol. 2011 Aug 18;119(3):p31-p39. [Epub ahead of print].

Pode Shakked N, Mark-Danieli M, Bahar S, Pri-Chen S, Tsvetkov P, Metsuyanim S, Goldstein RS, Rom-Gross E, Mor Y, Fridman E, Meir K, Goldmacher VS, Harari-Steinberg O, Dekel B. Prospective isolation, characterization and targeting of renal cancer stem cells lead to Wilms' tumor eradication.

Under revision in the Journal of Experimental Medicine.

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