Dr. Zvi Fuks, former Chairman of the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center, recruited me in 1984, to open up the Radiation Oncology Laboratory and we have been working together since on high single dose (SD) radiation effects on endothelial cells. Our studies showed that radiation induces apoptotic cell death in endothelial cells both in vitro and in vivo and that this apoptotic pathway is not p53 dependent, but rather dependent on activation of the enzyme Acid Sphingomyelinase (ASMase). We also showed that angiogenic factors such as bFGF, which protect the endothelial cells from radiation-induced apoptosis, rescued mice from radiation-induced pneumonitis and radiation-induced GI syndrome. In 1999 in collaboration with Dr. Kolesnick we showed that SD radiation induced apoptosis in response to DNA damage via activation of the enzyme Ceramide Synthase (CerS) via the de novo synthesis of ceramide within the mitochondria. We showed that CerS activation was negatively regulated by the Ataxia Telangiesctasia-Mutated (ATM) gene and that this pathway was activated in irradiated crypt stem cell clonogens (SCCs). Based on our data we suggested the hypothesis that endothelial apoptosis causes microvascular dysfunction, manifested as acute perfusion defects, which represses repair of DNA double strand breaks (DSBs) in crypt SCCs, determining the response to SD radiation in the generation of the GI syndrome. We further suggest that the genetic blueprint of DSB repair genes defines the SCC radiosensitivity, and that the radiation-induced epigenetic vascular component, controlled by the ceramide rheostat, down-modulates inherent repair function, determining the response phenotype. Based on this information we have begun development of a number of strategies to mitigate GI tract damage.
In addition since 1994, my program focuses on the role of DNA damage-induced apoptosis in human prostate cell lines LNCaP and CRW22Rv1, which are radioresistant, but TPA (phorbol ester), which reduces ATM levels serves as a radiosensitizer in these cells both in vitro and in vivo. Targeted disruption of ATM in prostate cancer cells leads to radiation-induced apoptosis via CerS signaling. Further identification of molecular targets within this pathway and development of specific reagents or small molecules aimed at ATM inactivation are the focus of ongoing studies in this program.
Recently we have shown that high dose (HD) chemotherapeutic drugs, like radiation, induces endothelial apoptosis, dependent on activation of the enzyme ASMase, and causes microvascular dysfunction in tumors, leading to tumor growth delay and tumor cures. We are currently testing whether the wave of microvascular dysfunction represses repair of DNA double strand breaks (DSBs) in these tumors and possible involvement of other mechanisms contributing to the tumor response. We are also determining whether HD chemotherapy generation of the GI syndrome might be due to the wave of microvascular dysfunction affecting crypt SCCs. Future studies will focus on the HD chemotherapy-induced endothelial apoptosis and microvascular dysfunction in metastatic models.
Selected Peer-Review Publications
Haimovitz-Friedman A, Kolesnick RN, Fuks Z. Modulation of the Apoptotic Response: Potential for Improving the Outcome in Clinical Radiotherapy. Seminars in Radiation Oncology, 1996; 6:273-283.
Haimovitz-Friedman A. Radiation-induced Signal Transduction and Stress Response. In: Radiation Research special issue commemorating the discovery of radium and polonium by Marie Curie in 1898. Radiat. Res. 1998; 150: S102-S108.
Fuks Z, Persaud R, Alfieri A, McLoughlin M, Schwartz J L, Cordon-Cardo C, Seddon AP, Haimovitz-Friedman A. Basic Fibroblast Factor Protects Endothelial Cells Against Radiation-Induced Programmed Cell Death in vitro and in vivo. Cancer Res.1994; 54: 2582-2590.
Haimovitz-Friedman A, Balaban N, McLaughlin M, Ehleiter D, Michaeli J, Fuks Z. Protein Kinase C Mediates Basic Fibroblast Growth Factor Protection of Endothelial Cells Against Radiation-Induced Apoptosis. Cancer Res. 1994; 54: 2591-2597.
Haimovitz-Friedman A, Kan C-C, Ehleiter D, Persaud R, McLaughlin M, Fuks Z. Ionizing Radiation Acts Directly on Cellular Membranes to Generate Ceramide and Initiate Apoptosis. J. Exp. Med. 1994; 180:525-535.
Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, Birrer MJ, Szabo E, Zon LI, Kyriakis JM, Haimovitz-Friedman A, Fuks Z, Kolesnick RN. Environmental stresses signal apoptosis through a ceramide-initiated SAPK/JNK-mediated cascade. Nature, 1996; 380:75-79.
Liao W C*, Haimovitz-Friedman A*, Persaud R, McLoughlin M, Ehleiter D, Zhang N, Gatei M, Lavin M, Kolesnick RN, Fuks Z. ATM inhibits DNA damage-induced apoptosis via ceramide synthase. J. Biol. Chem. 1999; 274: 17908-17917.
*Both authors contributed equally to this publication.
Garzotto M, Haimovitz-Friedman A, White-Jones M, Liao W-C, Huryk R, Heston DW, Cordon-Cardo C, Kolesnick RN, Fuks Z. Reversal of radiation resistance in LNCaP cells by targeting apoptosis through ceramide synthase. Can. Res., 1999, 59: 5194-520.
Paris F, Kang A, Capodieci P, Ehleiter D, Haimovitz-Friedman A, Cordon-Cardo C, Fuks Z, Kolesnick RN. Endothelial Apoptosis is the Primary Lesion Initiating Radiation Damage to the Intestines. Science, 2001 July 293: 293-297.
Paris F, Perez GI, Fuks Z, Haimovitz-Friedman A, Nguyen H, Bose M, Ilagan A, Hunt PA, Morgan WF, Tilly JL, Kolesnick RN. Sphingosine-1-phosphate preserves fertility in irradiated female mice without propagating genomic damage in offspring. Nat Med., 8 : 901-902, 2002.
Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, Fuks Z, Kolesnick R. Tumor response to low-dose radiotherapy regulated by endothelial cell apoptosis. Science, 300: 1155-1159, 2003.
Truman J-P, Gueven N, Lavin M, Leibel S, Kolesnick R, Fuks Z, Haimovitz-Friedman A. Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis. J Biol Chem 2005, 280: 23262-23272.
Chang H-J, Maj J, Paris FE, Xing HR, Zhang J, Truman J-P, Cordon-Cardo C, Haimovitz-Friedman A, Kolesnick R, Fuks Z. ATM regulates target switching to escalating doses of radiation in the intestines. Nat Med., 2005, 11: 484-490.
Rotolo J, Maj J, Feldman R, Ren D, Haimovitz-Friedman A, Cordon-Cardo C, Cheng E, Kolesnick R, Fuks Z. Bax and bak do not exhibit functional redundancy in mediating radiation-induced endothelial apoptosis in the intestinal mucosa. Int J Radiat Oncol Biol Phys., 2008, 70: 321-650.
Truman J-P, Rotenberg SA, Kang J-H, Lerman G, Fuks Z, Kolesnick R, and Haimovitz-Friedman A. PKCÎ± activation downregulates ATM and radio-sensitizes androgen-sensitive human prostate cancer cells in vitro and in vivo. Cancer Biology and Therapy 2009: 8(1): 54-63.