Our laboratory research interests focus on the pre-clinical development of cross complimentary approaches to integrate systemic therapies with radiotherapy through 1) elucidation of DNA damage response pathways 2) identification and characterization of novel radiosensitizers 3) development of tumor targeted approaches to improve the therapeutic ratio of radiotherapy. In contrast to current radiosensitization approaches, our strategies are biomarker driven and histologically agnostic. The overarching goal of our laboratory is to provide the preclinical rationale for translation to clinical trials of unique targeted systemic therapies in combination with radiotherapy.
A major focus of the Advani Lab is on understanding and overcoming radioresistance. Dr. Advani and colleagues have attacked this problem on two fronts: 1) identifying novel cell signaling pathways involved in cellular response to radiation 2) targeting delivery of highly potent radiosensitizers to tumors.
The focus on cell signaling pathways involved in radioresistance centers on a PAK-RAF signaling axis that plays a role in mediating DNA damage repair following radiotherapy. Dr. Advani and colleagues demonstrated that non-canonical, kinase independent functions of RAF mediates cell cycle progression and radioresistance through phosphorylation of CRAF by PAK1. Lab researchers also focus on developing tumor targeted delivery approaches to ultra-potent tumoricidal drugs that have the dual advantage of also radiosensitizing.
Yu V, Rahimy M, Korrapati A, Xuan Y, Zou AE, Krishnan A, Tsui T, Aguilera JA, Advani S, Alexander LE, Brumund KT, Wang-Rodriguez J, Ongkeko WM. Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines. Oral Oncol. 2015 pii: S1368-8375(15)00362-0. doi: 10.1016/j.oraloncology.2015.10.018
Paravati AJ, Hawkins PG, Martin AN, Mansy G, Rahn DA, Advani SJ, Hoisak J, Dragojevic I, Martin PJ, Miller CJ, Sanghvi P. Clinical and cosmetic outcomes in patients treated with high-dose-rate electronic brachytherapy for nonmelanoma skin cancer. Pract Radiat Oncol. 2015. S1879-8500(15)00232-5. doi: 10.1016/j.prro.2015.07.002.
Advani SJ, Camargo MF, Seguin L, Mielgo A, Anand S, Hicks AM, Aguilera J, Franovic A, Weis SM, Cheresh DA. Kinase-independent role for CRAF-driving tumour radioresistance via CHK2. Nature Communications 2015 6:8154. doi: 10.1038/ncomms9154.
Raju SC, Hauff SJ, Lemieux AJ, Orosco RK, Gross AM, Nguyen LT, Savariar E, Moss W, Whitney M, Cohen EE, Lippman SM, Tsien RY, Ideker T, Advani SJ, Nguyen QT. Combined TP53 mutation/3p loss correlates with decreased radiosensitivity and increased matrix-metalloproteinase activity in head and neck carcinoma. Oral Oncol. 2015 51:470-475. doi: 10.1016/j.oraloncology.2015.01.014.
Buckel L, Savariar EN, Crisp JL, Jones KA, Mier Hicks A, Scanderbeg DJ, Nguyen QT, Sicklick JK, Lowy AM, Tsien RY, Advani SJ. Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery. Cancer Res. 2015 75:1376-1387. doi: 10.1158/0008-5472.CAN-14-1931.
Buckel L, Advani SJ, Frentzen A, Zhang Q, Yu YA, Chen NG, Ehrig K, Stritzker J, Mundt AJ, Szalay AA. Combination of fractionated irradiation with anti-VEGF expressing vaccinia virus therapy enhances tumor control by simultaneous radiosensitization of tumor associated endothelium. International Journal of Cancer 2013 133:2989-2999. doi: 10.1002/ijc.28296.
Advani SJ, Buckel L, Chen NG, Scanderbeg DJ, Geissinger U, Zhang Q, Yu YA, Aguilar RJ, Mundt AJ, Szalay AA. Preferential replication of systemically delivered oncolytic vaccinia virus in focally irradiated glioma xenografts. Clinical Cancer Research 2012 18:2579-2590. doi:10.1158/1078-0432.CCR-11-2394.
Mielgo A, Seguin L, Huang M, Camargo MF, Anand S, Franovic A, Weis SM, Advani SJ, Murphy EA, Cheresh DA. A MEK-independent role for CRAF in mitosis and tumor progression. Nature Medicine 2011 17:1641-1645. doi:10.1038/nm.2464.
Advani SJ, Markert JM , Sood R, Samuel S, Gillespie Y, Shao M, Roizman B, Weichselbaum RR. Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1. Gene Therapy 2011 18:1098-1102. doi:10.1038/gt2011.61.
Kesari S, Advani SJ, Lawson JD, Kahle KT, Ng K, Carter B, Chen CC. DNA damage response and repair: insights into strategies for radiation sensitization of gliomas. Future Oncol 2011 7:1335-1346. doi:10.2217/fon.11.111.