Research Program

The goal of the research performed in the Ronen lab is to develop and mechanistically validate robust noninvasive translatable magnetic resonance (MR)–based biomarkers that can be used to identify oncogenic events associated with cancer, and to monitor response to chemotherapy and emerging targeted therapies.

To this end, our research uses multinuclear MR spectroscopy (MRS), imaging (MRI) and spectroscopic imaging (MRSI) to probe preclinical cell and animal models of cancer. Putative biomarkers are mechanistically validated using established biochemical, cell and molecular biological methods.

Current Research Projects

Choline-containing metabolites as biomarkers of cancer (Funding: NIH RO1)

Clinical studies demonstrate that phosphocholine (PC) and total-choline-containing metabolite (tCho) levels are elevated in virtually all cancer types. Research in the lab has shown that PC synthesis is modulated by signaling via Ras, MAPK and PI3K. To further our understanding of the link between oncogenic signaling and PC levels, we are investigating the precise mechanism by which oncogenes affect choline metabolism in breast, prostate and brain cancer. This work will serve to validate PC as a biomarker of oncogenic transformation and will test the value of PC as a marker of response to novel oncogene-targeted therapies.

Pyruvate metabolism as a biomarker of PI3K signaling in cancer (Funding: NIH RO1)

The PI3K pathway is mutated in over 30% of human cancers and in 88% of glioblastoma (GBM) cases. We hypothesized that because the PI3K pathway mediates the expression of enzymes controlling the glycolytic pathway, probing the last step of the glycolytic pathway using hyperpolarized ¹³C MRS will inform on the status of PI3K signaling. We have confirmed this hypothesis and shown that the pyruvate to lactate conversion is inhibited following PI3K inhibition in breast cancer and some GBM cells. Current research is aimed at confirming the  generality of our findings in GBM cells. Future work will focus on translating our findings to animal models and subsequently to patients with GBM. This research will validate a novel radiation free imaging method to monitor the effect of PI3K inhibitors in vivo.

Monitoring the mutational status and activity of isocitrate dehydrogenase (IDH) in glioma (Funding: NIH R21, UCSF Brain Tumor Spore and Senate)

Mutant  forms of IDH have recently been discovered in over 70% of grade II, III and secondary GBM. Recent studies indicate that the IDH mutation is an early oncogenic event and inhibiting mutant IDH activity is being considered as a novel therapeutic approach in the treatment of tumors that harbor this mutation. Our wok is focused on developing and validating hyperpolarized ¹³C and ¹H MRS-based approaches for monitoring IDH mutational status and activity. These approaches could help both in development of novel IDH inhibitors and in monitoring the effect of such inhibitors in future trials.

Determining the metabolomic profile of pancreatic cancer (Funding:Schwartz Pancreatic Cancer fund)

By investigating cell lines, pancreatic juices and patients biopsies, this pilot study is focused on identifying a characteristic ¹H MRS-based metabolomic signature of pancreatic cancer.

Recent Related Publications

1. Chung YL, Troy H, Banerji U, Jackson LE, Walton MI, Stubbs M, Griffiths JR, Judson IR, Leach MO, Workman P, Ronen SM. Magnetic resonance spectroscopic pharmacodynamic markers of the heat shock protein 90 inhibitor 17-allylamino,17-demethoxygeldanamycin (17AAG) in human colon cancer models. J Natl Cancer Inst.  2003 Nov 95(21):1624-33.
2. Beloueche-Babari M, Jackson LE, Al-Saffar NM, Workman P, Leach MO, Ronen SM. Magnetic resonance spectroscopy monitoring of mitogen-activated protein kinase signaling inhibition. Cancer Res. 2005 Apr 65(8):3356-63.
3. Beloueche-Babari M, Jackson LE, Al-Saffar NM, Eccles SA, Raynaud FI, Workman P, Leach MO, Ronen SM. Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells. Mol Cancer Ther.  2006 Jan 5(1):187-96.
4. Sankaranarayanapillai M, Tong WP, Maxwell DS, Pal A, Pang J, Bornmann WG, Gelovani JG, Ronen SM. Detection of histone deacetylase inhibition by noninvasive magnetic resonance spectroscopy. Mol Cancer Ther. 2006 May 5(5):1325-34.
5. Ross J, Najjar AM, Sankaranarayanapillai M, Tong WP, Kaluarachchi K, Ronen SM. Fatty acid synthase inhibition results in a magnetic resonance-detectable drop in phosphocholine. Mol Cancer Ther.  2008 Aug 7:2556-2565.
6. Sankaranarayanapillai M, Tong WP, Yuan Q, Bankson JA, Dafni H, Bornmann WG, Soghomonyan S, Pal A, Ramirez MS, Webb D, Kaluarachchi K, Gelovani JG, Ronen SM. Monitoring histone deacetylase inhibition in vivo: noninvasive magnetic resonance spectroscopy method. Mol Imaging.  2008 Mar-Apr 7(2):92-100.
7. Dafni H, Kim SJ, Bankson JA, Sankaranarayanapillai M, Ronen SM. Macromolecular dynamic contrast-enhanced (DCE)-MRI detects reduced vascular permeability in a prostate cancer bone metastasis model following anti-platelet-derived growth factor receptor (PDGFR) therapy, indicating a drop in vascular endothelial growth factor receptor (VEGFR) activation. Magn Reson Med.  2008 Sep 60(4):822-833.
8. Ward CS, Venkatesh HS, Chaumeil MM, Brandes AH, Vancriekinge M, Dafni H, Sukumar S, Nelson SJ, Vigneron DB, Kurhanewicz J, James CD, Haas-Kogan DA, Ronen SM. Noninvasive Detection of Target Modulation following Phosphatidylinositol 3-Kinase Inhibition Using Hyperpolarized ¹³C Magnetic Resonance Spectroscopy. Cancer Res. 2010 Feb 70(4):1296-305.
9. Koul D, Shen R, Kondo Y, Bankson J, Ronen SM, Kirkpatrick DL, Powis G, Yung, WKA. Cellular and in vivo activity of a novel PI3K inhibitor PX-866 for treatment of human glioblastoma. Neuro-Oncology. 2010 Jun;12(6):559-69
10. Dafni H, Larson PE, Hu S, Yoshihara HA, Ward CS, Venkatesh HS, Wang C, Zhang X, Vigneron DB, Ronen SM. Hyperpolarized ¹³C spectroscopic imaging informs on hypoxia-inducible factor-1 and myc activity downstream of platelet-derived growth factor receptor. Cancer Res.,  2010 Oct 1;70(19):7400-10
11. Brandes AH, Ward CS, Ronen SM. 17-allyamino-17-demethoxygeldanamycin treatment results in a magnetic resonance spectroscopy-detectable elevation in choline-containing metabolites associated with increased expression of choline transporter SLC44A1 and phospholipase A2. Breast Cancer Res. 2010 Oct 14;12(5):R84
12. Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, Debnath J. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell. 2011 Jan 15;22(2):165-78
13. Park I, Bok R, Ozawa T, Phillips JJ, James CD, Vigneron DB, Ronen SM, Nelson SJ. Detection of early response to temozolomide treatment in brain tumors using hyperpolarized ¹³C MR metabolic imaging. J Magn Reson Imaging. 2011 Jun;33(6):1284-90
14. Lodi A, Ronen SM. Magnetic resonance spectroscopy detectable metabolomic fingerprint of response to antineoplastic treatment. PLoS One. 2011;6(10):e26155
15. Glunde K, Bhujwalla ZM, Ronen SM. Choline metabolism in malignant transformation. Nat Rev Cancer. 2011 Nov 17;11(12):835-48
16. Chaumeil MM, Ozawa T, Park I, Scott K, James CD, Nelson SJ, Ronen SM. Hyperpolarized  ¹³C MR spectroscopic imaging can be used to monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma. Neuroimage. 2012 Jan 2;59(1):193-201
17. Su JS, Woods SM, Ronen SM. Metabolic consequences of treatment with AKT inhibitor perifosine in breast cancer cells. NMR Biomed. 2012 Feb;25(2):379-88
18. Venkatesh H, Chaumeil MM, Ward CS, Haas-Kogan DA, James CD, Ronen SM, Reduced phosphocholine and hyperpolarized lactate provide MR biomarkers
    of PI3K/Akt/mTOR inhibition in GBM. Neuro-oncology. 2012 Mar;14(3):315-25
19. Chaumeil MM, Gini B, Yang H, Iwanami A, Sukumar S, Ozawa T, Pieper RO, Mischel PS, James CD, Berger MS, Ronen SM. Longitudinal evaluation of MPIO-labeled stem cell biodistribution in glioblastoma using high resolution and contrast-enhanced MR imaging at 14.1Tesla. Neuro Oncol. 2012 Jun 4. [Epub ahead of print]

20. Dafni H, Burghardt AJ, Majumdar S, Navone NM, Ronen SM.Vascular patterning and permeability in prostate cancer models with differing osteogenic properties. NMR Biomed. 2012 Jun;25(6):843-51

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