My Lab principal research interests include elucidation of the mechanism of action of radiation-induced microvasculature dysfunction and modulation of this response in normal tissues to minimize its side effects. We have previously showed that radiation induces apoptotic cell death in endothelial cells both in vitro and in vivo is not p53 dependent, but rather dependent on activation of the enzyme Acid Sphingomyelinase (ASMase). The vulnerability of endothelium to radiation-induced apoptosis was linked to a 20-fold higher level of ASMase expression in endothelium than in any other mammalian cell. In our initial studies we provided the first conclusive evidence that apoptotic signaling can be generated by interaction of ionizing radiation with cellular membranes and suggested an alternative to the hypothesis that direct DNA damage mediates radiation-induced cell kill.
Subsequently, using a genetic model of ASMase-deficient mice we showed that these mice were resistant to radiation-induced pneumonitis, radiation-induced gastrointestinal syndrome (GI), and radiation-induced xerostomia via activation of this pathway. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which regulates the ability of tissues stem cells to process potentially lethal damage directly induced in them by radiation. In addition, we were able to protect the wild type mice from radiation-induced pneumonitis and GI by pretreatment with bFGF, which protected the radiation-induced microvascular dysfunction.
Recently we initiated studies on partial tumor volume exposure to single high dose radiation-therapy (SDRT) in an attempt to determine whether suboptimal tumor coverage due to dose constraints can be potentially curative. In two tumor models, responses were similar in the fully and partially irradiated tumors, and hemi-RT initiated an “early” adaptive immune response dependent on CD8+ T cells infiltration of the tumors and on the expression of ICAM adhesion molecules on the endothelium.
In addition, we were able to demonstrate for the first time that radiation induces excessive NADPH oxidases (NOX) activation and reactive oxygen species (ROS) generation in endothelial cells and that Sildenafil protects them from this oxidative stress. This study and other studies we published recently,demonstrate that ROS generation is an indispensable mediator of SDRT-induced ischemia/reperfusion pathobiology in tumors. They also demonstrated the transient and immediate O2•- generation and the subsequent accumulation of peroxynitrite (OONO-) after SDRT, which resulted in impaired endothelial function.
Following are publications describing our most recent work:
1. Markovsky E, Budhu S, Samstein RM, Li H, Russell J, Zhang Z, Drill E, Bodden C, Chen Q, Powell SN, Merghoub T, Wolchok JD, Humm J, Deasy JO, Haimovitz-Friedman A. An Anti-Tumor Immune Response is Evoked By Partial-Volume Single Dose Radiation in Two Murine Models. Int J Radiat Oncol Biol Phys. 2018 Oct 17. pii: S0360-3016(18)33860-4. doi: 10.1016/j.ijrobp.2018.10.009. [Epub ahead of print] PMID: 30342090
2. Marciscano AE, Haimovitz-Friedman A, Lee P, Tran PT, Tome WA, Guha C, Spring Kong FM, Shangal A, El Naga I, Rimner A, Marks LB, Formenti SC, DeWeese T. Immunomodulatory Effects of Stereotactic Body Radiation Therapy. Preclinical Insights and Clinical Opportunities. Int J Radiat Oncol Biol Phys. 2019 Mar 2. pii: s0360-3016(19)30290-1. Doi: 10.1016/j.ijrobp.2019.02.046.
3. Truman JP, Garcia-Barros M, Kaag M, Hambardzumyan D, Stancevic B, Chan M, Fuks Z, Kolesnick R, Haimovitz-Friedman A. Endothelial Membrane Remodeling is Obligate for Anti-angiogenic Radiosensitization during Tumor Radiosurgery. PLoS ONE 2010 Sept 30;5(8): e12310.
4. Hallahan DE, Haimovitz-Friedman A, Kufe DW, Fuks Z, Weichselbaum RR. The role of cytokines in radiation biology. In: Important Advances in Oncology. Ed. VT DeVita, S Hellman and SA Rosenberg. JB Lippincott Co., Philadelphia. 1993: 71-80.
5. Shamay Y, Elkabets M, Li H, Shah J, Brook S, Wang F, Adler K, Baut E, Scaltriti M, Jena PV, Gardner EE, Poirier JT, Rudin CM, Baselga J, Haimovitz-Friedman A, Heller DA. P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Sci Transl Med. 2016 Jun 29;8(345): 345ra87. doi: 10.1126/scitranslmed.aaf7374. PMID: 27358497
6. Mizrachi A, Cotrim AP, Katabi N, Mitchel JB, Verheij M, Haimovitz-Friedman A. Radiation-induced microvascular injury as a mechanism of salivary gland hypofunction and potential target for radioprotectors. Radiat Res. 2016 Aug; 186(2):189-95. doi: 10.1667/RR14431.1. PMID: 27459704
7. Jacobi J, Garcia-Barros M, Rao S, Rotolo JA, Thompson C, Mizrachi A, Manova K, Fuks Z, Kolesnick R, Haimovitz-Friedman A. Targeting acid sphingomyelinase with anti-angiogenic chemotherapy. Cell Signal.2016 Oct 1. pii: S0898-6568(16)30236-4. doi: 10.1016/j.cellsig.2016.09.010. [Epub ahead of print] PMID: 27702691
8. Mizrachi A, Shamay Y, Shah J, Brook S, Soong J, Rajasekhar VK, Humm JL, Healey JH, Powell SN, Baselga J, Heller DA, Haimovitz-Friedman A, Scaltriti M. Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma. Nat Commun. 2017 Feb 13;8:14292. doi: 10.1038/ncomms14292. PMID: 28194032.
9. van Hell AJ, Haimovitz-Friedman A, Fuks Z, Tap WD, Kolesnick R. Gemcitabine kills proliferating endothelial cells exclusively via acid sphingomyelinase activation. Cell Signal. 2017 Feb 24; 34:86-91. doi:10.1016/j.cellsig.2017.02.021. [Epub ahead of print] PMID: 28238856. DOI: 10.1016/j.cellsig.2017.02.021
10. Russell J, Pillarsetty N, Kramer RM, Romesser PB, Desai P, Haimovitz-Friedman A, Lowery MA, Humm JL. In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2’-deoxy-2’-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models. Mol Imaging Biol. 2017 Mar 27. doi: 10.1007/s11307-017-1078-6. [Epub ahead of print] PMID: 28349292.
11. Wang F, Li H, Markovsky E, Glass R, de Stanchina E, Powell SN, Schwartz GK, Haimovitz-Friedman A. Pazopanib radio-sensitization of human sarcoma tumors. Oncotarget. 2018 Feb 6;9(10):9311. doi: 10.18632/oncotarget.24281. eCollection 2018 Feb 6. PMID: 29507692
12. Markovsky E, de Stanchina E, Itzkowitz A, Haimovitz-Friedman A, Rotenberg SA. Phosphorylation state of Ser165 in α-tubulin is a toggle switch that controls proliferating human breast tumors. Cellular signaling. 2018 Aug 31; doi:10.1016/j.cellsig.2018.08.021.
13. Bodo S, Campagne C, Thin TH, Higginson DS, Vargas HA, Hua G, Fuller JD, Ackerstaff E, Russell J, Zhang Z, Klingler S, Cho H, Kaag MG, Mazaheri Y, Rimner A, Manova-Todorova K, Epel B, Zatcky J, Cleary CR, Rao SS, Yamada Y, Zelefsky MJ, Halpern HJ, Koutcher JA, Cordon-Cardo C, Greco C, Haimovitz-Friedman A, Sala E, Powell SN, Kolesnick R, Fuks Z. Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury. J Clin Invest. 2019 Jan 14. pii: 97631. doi: 10.1172/JCI97631.
14. Wortel RC, Mizrachi A, Li H, Markovsky E, Enyendi B, Jacobi J, Brodsky O, Cao J, Lippert AR, Incrocci L, Mulhall JP, Haimovitz-Friedman A. Sindenafil Protects Enndothelial Cells From Radiation-Induced Oxidative Stress. J Sex Med. 2019 Nov;16(11): 1721-1733. Doi: 10.1016/j.jsxm.2019.08.015. Epub 2019 Oct 1.
15. Barasch A, Li H, Rajasekhar VK, Raber-Durlacher J, Epstein JB, Caroll J, Haimovitz-Friedman A.Photobiomodulation effects on head and neck squamous cell carcinoma (HNSCC) in an orthotopic model. Supoort Care Cancer. 2019 Nov 8;. Doi: 10.1007/s00520-019-05060-0. [Epub ahead of print}
PubMed PMID: 31705378.
16. Haimovitz-Friedman A, Mizrachi A, Jaimes EA. Manipulating Oxidative Stress Following Ionizing Radiation. J Cell Signal. 2020;1(1):8-13. doi: 10.33696/signaling.1.003.