Epithelioid sarcoma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Overview

The predominant therapy for epithelioid sarcoma is surgical resection. Adjunctive chemotherapy, radiation, and chemoradiation may be required.

Medical Therapy

Chemotherapy

Radiation Therapy

  • Radiation Therapy was used for limb salvage therapy.
  • Radiation therapy is also a treatment option when tumors are deemed inoperable or wide surgical margins are not achievable.
  • Radiation therapy in combination with chemotherapy has so far resulted in only minimal improvements to response rates.
  • Trials with brachytherapy (an internal radiation treatment that delivers a high dose of radiation directly to the tumor and is thought to have fewer long-term side effects) have produced some positive results.

Complications of Radiation Therapy

New Therapeutic Strategies

New chemo-therapies

  • New chemotherapies are being explored in current clinical trials for epithelioid sarcoma, although, thus far, none has shown significant improvement over the efficacy of doxorubicin/ifosfamide.
  • These new agents include gemcitabine, pazopanib, cixutumumab, temozolamide, dasatanib, bevacizumab, taxanes, and vinorelbine.
  • Aldoxorubicin is a new pro-drug of doxorubicin. Doxorubicin is the standard of care for advanced or metastic epithelioid sarcoma, but has dose-limiting toxicities, namely acute and chronic cardiac toxicity.[1][2]
  • Doxorubicin has achieved response rates in the 12-23% range for patients with soft tissue sarcomas.
  • Aldoxorubicin is a new version of doxorubicin that is designed to safely deliver a higher dose of the drug directly to the tumor, resulting in increased efficacy and less toxicity.
    • It works by entering the bloodstream, binding to the albumin in the blood, traveling throughout the body, and releasing a doxorubicin payload when it encounters the acidic microenvironment of a tumor.[3]
  • Several phase I and II studies are ongoing, and, thus far at least, little if any cardiac toxicity has been observed.
  • A maximum tolerated dose of aldoxorubicin has been established at 3.5 times the MTD of doxorubicin, and studies have indicated increased response rates for patients with soft tissue sarcomas.
  • What is unknown at this time are the potential long-term side-effects of this increased dose of doxorubicin.
  • Several studies have shown increased risk of the development of secondary cancers associated with exposure to high-dose anthracyclines (such as doxorubicin).[4]
  • TH-302 is another novel prodrug in current development. It targets tumor hypoxia, a common event in tumorigenesis where the tumor microenvironment is depleted of oxygen and becomes hypoxic.[5]
  • Hypoxic niches in tumors tend to harbor slower-growing cancer cells, making many chemotherapies ineffective in these areas.
  • TH-302 directly targets these deep hypoxic regions, and once within them, it releases a cytotoxic payload of bromo-isophosphoramide mustard directly to the cancer cells.
  • Given that epithelioid sarcoma is a slow-growing tumor, it is reasonable to hypothesize that epithelioid sarcoma tumors would be highly hypoxic and show a favorable response to TH-302.
  • Several studies have observed increased efficacy of TH-302 when the hypoxic tumor microenvironment has been exasperated.[6]
  • Several phase I, II, and III trials with TH-302 and TH-302 in combination with doxorubicin are ongoing, and promising results have thus far been observed.[7][8]

Immunotherapies

  • Immunotherapy is the strategy of using the body’s own immune system to fight cancer. It usually involves “training” or “tweaking” the immune system so that it can better recognize and reject cancer cells.
  • Different immunotherapies can include manipulation of the body’s T-cells, NK cells, or Dendritic cells so they are more effective against cancer cells.
  • Vaccine therapy is perhaps the immunotherapeutic strategy with the most ongoing exploration in sarcomas at the current time, although, thus far at least, little evidence has emerged indicating that active vaccination alone can lead to tumor regression.[9][10]
  • Multiple techniques and treatment strategies are currently being studied in an effort to improve the objective response rate of vaccine therapy.[10]
  • Vaccines can deliver various tumor-associated factors (tumor antigens) to the immune system, resulting in a natural antibody and T-cell response to the tumor.[10][11]
  • Adoptive immunotherapy seeks to expand a population of the body’s T-cells that will recognize a specific tumor antigen. T-cells can be harvested and then expanded and genetically manipulated to recognize certain tumor markers.[10][11]
    • In an interesting case study, a patient with advanced epithelioid sarcoma who had failed multiple therapies showed a strong response to expanded lymphocytes and natural killer cells.[12]
  • Immune checkpoint inhibitors have recently shown promise against several cancers and may hold promise against sarcomas as well.
  • Tumors often evolve during disease progression, and they can develop an expression of inhibitory proteins that deter recognition by the immune system and allow the tumor to escape immune surveillance.[9]
  • By targeting these inhibitory proteins, a pathway is opened for the immune system to recognize the tumor.
  • Two of these inhibitory proteins that have been studied recently are CTLA-4 and PD1, and drugs targeting these proteins are in development and showing some promise.[9]

Anti-Angiogenic Therapies

  • Several anti-angiogenic agents are being explored in epithelioid sarcoma, a cancer that likely relies on angiogenesis for survival and progression.
  • These agents interfere with various pro-angiogenic factors, several of which are known to be over-expressed in epithelioid sarcoma (VEGF and EGFR for example).[13][14]
  • Tumors require a blood supply to provide them with oxygen and nutrients necessary for their survival.
  • As tumors expand and grow, they send out various signals (such as HIF1) that encourage new blood vessel development to the tumor.[15]
  • Anti-angiogenic agents, such as bevacizumab, pazopanib, and sunitinib, attempt to slow or block the growth of tumors by essentially cutting off their blood supply.

Targeted Therapies

  • LEE 011 (Ribociclib) is a newer drug that is an inhibitor of cyclin D1/CDK4 and CDK6.[16]
  • Cyclin-dependent kinases (CDKs) 4 and 6 are enzymes that have been shown to promote cell division and multiplication in both normal and cancer cells.
  • Many cancer cells have shown abnormalities that increase the activity of CDK4, leading to the inactivation of certain tumor suppressor genes.[16][17]
  • This has led to the idea that inhibiting CDK4 will slow the growth of tumors by reactivating these tumor suppressors. LEE 011 is currently in phase I development for several indications, including neuroblastoma and malignant rhabdoid tumor (which is also characterized by SMARCB1 mutations).
  • LEE 011 has been shown to be well-tolerated, although its best response as a single agent thus far has been stable disease.[18]
  • When used in combination with other drugs (such as an ALK or an MEK inhibitor, LEE 011 has been shown to have a synergistic effect, resulting in improved responses.[19][20]
  • Again, this is likely a result of “crosstalk” between signaling pathways.
  • Simply blocking one pathway in cancer tumorigenesis can sometimes result in “tumor compensation,” where the tumor compensates for the blocked signaling pathway by utilizing other pathways to survive.
  • By blocking several pathways at once, it is thought that the tumor is less able to compensate, and a greater anti-tumor response is often observed.
  • It is also of interest that utilizing LEE 011 in combination with other agents has been shown to reduce the development of resistance to these agents.[16]
  • In other words, cancer’s development of drug resistance can be mitigated with the addition of LEE 011 to the therapeutic regime.
  • Tyrosine kinase inhibitors (such as sunitinib, pazopanib, and dasatinib) have shown some effect against several cancer types, most notably Imatinib-mesylate in gastrointestinal stromal tumors (GISTs).[21]
  • Tyrosine kinase (a subclass of protein kinases) is an enzyme that transfers a phosphate group from an ATP molecule to a protein in a cell.[22]
    • It functions as an “on” or “off” switch for many cellular functions, including signaling within the cell, and cell division.
  • Tyrosine kinases can contain mutations that cause them to become constitutively active, or stuck in the “on” position, resulting in unregulated cell division (a hallmark of cancer).[23]
  • Tyrosine kinase Inhibitors block the action of these enzymes.
  • Tyrosine kinase inhibitors have been shown to inhibit the VEGF, EGFR, and MET, pathways that are frequently over-expressed in epithelioid sarcoma.[22]
  • They also can be used against the c-KIT and JAK-STAT signaling pathways, which are involved in many cancers and may be involved in epithelioid sarcoma. [22]
  • Temsirolimus is a tyrosine kinase inhibitor that blocks the effects of the mTOR protein and inhibits the mTOR pathway.
  • Interestingly, because of crosstalk between cell signaling pathways, it has been shown that, while interfering with the mTOR pathway alone produces only limited results in halting tumorigenesis, inhibiting both the mTOR and the EGFR pathways concurrently shows an increased effect.[22]
  • Selective inhibitors of nuclear export (SINE) compounds, such as selinexor and CBS9106, are being investigated in several sarcomas and have recently shown promising results across a broad spectrum of both hematological malignancies and solid tumors.[24][25]
  • These compounds work by blocking the export of tumor suppressor genes from the cell’s nucleus to the cell’s cytoplasm, where they are rendered nonfunctional.[26][24][27]
  • Exportin 1 (aka XPO1 or CRM1) is a nuclear export protein responsible for the export of over 200 proteins, including the vast majority of tumor suppressor proteins.[24]
  • For tumor suppressor genes to carry out their normal function (appropriately initiating apoptosis), they must be located in the nucleus of the cell.[26]
  • Many cancer cells have been shown to express high levels of exportin1, resulting in the increased export of tumor suppressor proteins out of the nucleus and therefore counteracting the natural apoptic processes that protect the body from cancer. [24][27]
  • SINE compounds prevent the transport of these tumor suppressor proteins out of the nucleus, allowing them to function normally and encourage apoptosis.
  • Recently, researchers have observed a synergistic effect when using SINE compounds in combination with traditional chemotherapies (such as doxorubicin).[28]
  • Of interest with respect to epithelioid sarcoma and other diseases characterized by the loss of INI1 function, it has been demonstrated that a loss of INI1 expression can result in the “unmasking” of a nuclear export signal, resulting in the transport of tumor suppressor proteins out of the nucleus of the cell, thus favoring tumorigenesis.[29]
  • It is therefore reasonable to suspect that a SINE inhibitor would show efficacy against epithelioid sarcoma, as the disease is characterized by a loss of INI1 function.
  • Histone deacetylase (HDAC) inhibitors, such as vorinostat, have shown some promise in epithelioid sarcoma.
  • Researchers in Texas are investigating whether or not HDAC inhibitors can reverse the loss of INI1 function that is characteristic of epithelioid sarcoma.
  • These include sulphorphane, indole-3-carbinol, and phenethyl isothiocyanates, found in broccoli, kale, and watercress, and epigallocatecehin-3-gallate, found in green tea.

Targeting the Cancer Stem Cell

  • Cancer stem cells (or cancer-initiating cells) are thought to be a small population of cells within the tumor that are directly responsible for tumor formation.
  • They are thought to be resistant to treatment and to have the ability to form all the cells needed for tumor development.
  • They are suspected to be a major contributing factor in cancer progression and relapse after treatment.
  • Certain “stem-like” cells have been found in epithelioid sarcoma that is marked by CD109 (cluster of differentiation 109), providing a potentially drug-able target on the cancer stem cell for the disease.
  • Certain challenges to targeting CD109 do exist, however, as CD109 is expressed in other areas of the body and not only in tumor cells.

Oncolytic Viral Therapy

  • Oncolytic viral therapy is an emerging cancer therapy that attempts to infect cancer cells with a genetically engineered virus that can penetrate the DNA of the cell.
  • The virus then
  • 1.) Does direct damage to the cancer cell
  • 2.) Is spread throughout the cells of the tumor via cellular (DNA) multiplication (tumor cell division and replication)
  • 3.) Provides a target for a direct immune response from the patient.[30]
  • CGTG-102 (developed by Oncos Therapeutics) is an adenovirus currently in orphan drug status for soft tissue sarcomas. It is modified to selectively replicate in p16/Rb-defective cells, which include most human cancer cells. In addition, CGTG-102 codes for the granulocyte–macrophage colony-stimulating factor (GM-CSF),[31][32] a potent immunostimulatory molecule. It has been noted that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect but strongly relies on the induction of an endogenous immune response against transformed cells.[31][30] Superior anticancer effects have been observed when oncolytic viruses are engineered to express (or be co-administered with) immunostimulatory molecules such as GM-CSF.[31]
  • While the CGTG-102 oncolytic adenovirus has shown efficacy as a single agent against several soft tissue sarcomas, it would also be appealing to use in combination with other regimes, as oncolytic viruses have demonstrated very little overlap in side effects with traditional therapies such as chemotherapy and radiation.[31][30] CGTG-102 has recently been studied in combination with doxorubicin, and a synergistic effect was observed.[33] At least part of doxorubicin’s mechanism of action is as an inducer of immunogenic cell death, and it has been suggested that immune response contributes to its overall anti-tumor activity. Doxorubicin has been shown to increase adenoviral replication in soft tissue sarcoma cells as well,[33] potentially contributing to the observed synergistic effect in the virus/doxorubicin combination.
  • Telomelysin (OBP-301) is an adenovirus that targets telomerase,[34] an enzyme that is expressed in practically all cancer cells but not in normal cells. OBP-301 has been studied in epithelioid sarcoma and shown to promote apoptosis and cell death [.[34]

References

  1. ↑ Lefrak, Edward A.; Piťha, Jan; Rosenheim, Sidney; Gottlieb, Jeffrey A. (1973). "A clinicopathologic analysis of adriamycin cardiotoxicity". Cancer. 32 (2): 302–14. doi:10.1002/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2. PMID 4353012.
  2. ↑ Lipshultz, Steven E.; Colan, Steven D.; Gelber, Richard D.; Perez-Atayde, Antonio R.; Sallan, Stephen E.; Sanders, Stephen P. (1991). "Late Cardiac Effects of Doxorubicin Therapy for Acute Lymphoblastic Leukemia in Childhood". New England Journal of Medicine. 324 (12): 808–15. doi:10.1056/NEJM199103213241205. PMID 1997853.
  3. ↑ Chawla, Sant P.; Chua, Victoria S.; Hendifar, Andrew F.; Quon, Doris V.; Soman, Neelesh; Sankhala, Kamalesh K.; Wieland, D. Scott; Levitt, Daniel J. (2015). "A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma". Cancer. 121 (4): 570–9. doi:10.1002/cncr.29081. PMID 25312684.
  4. ↑ Henderson, T. O.; Whitton, J.; Stovall, M.; Mertens, A. C.; Mitby, P.; Friedman, D.; Strong, L. C.; Hammond, S.; Neglia, J. P.; Meadows, A. T.; Robison, L.; Diller, L. (2007). "Secondary Sarcomas in Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study". Journal of the National Cancer Institute. 99 (4): 300–8. doi:10.1093/jnci/djk052. PMID 17312307.
  5. ↑ Meng, F.; Evans, J. W.; Bhupathi, D.; Banica, M.; Lan, L.; Lorente, G.; Duan, J.-X.; Cai, X.; Mowday, A. M.; Guise, C. P.; Maroz, A.; Anderson, R. F.; Patterson, A. V.; Stachelek, G. C.; Glazer, P. M.; Matteucci, M. D.; Hart, C. P. (2012). "Molecular and Cellular Pharmacology of the Hypoxia-Activated Prodrug TH-302". Molecular Cancer Therapeutics. 11 (3): 740–51. doi:10.1158/1535-7163.MCT-11-0634. PMID 22147748.
  6. ↑ Wojtkowiak, Jonathan W; Cornnell, Heather C; Matsumoto, Shingo; Saito, Keita; Takakusagi, Yoichi; Dutta, Prasanta; Kim, Munju; Zhang, Xiaomeng; Leos, Rafael; Bailey, Kate M; Martinez, Gary; Lloyd, Mark C; Weber, Craig; Mitchell, James B; Lynch, Ronald M; Baker, Amanda F; Gatenby, Robert A; Rejniak, Katarzyna A; Hart, Charles; Krishna, Murali C; Gillies, Robert J (2015). "Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302". Cancer & Metabolism. 3 (1): 2. doi:10.1186/s40170-014-0026-z. PMC 4310189. PMID 25635223.
  7. ↑ Chawla, S. P.; Cranmer, L. D.; Van Tine, B. A.; Reed, D. R.; Okuno, S. H.; Butrynski, J. E.; Adkins, D. R.; Hendifar, A. E.; Kroll, S.; Ganjoo, K. N. (2014). "Phase II Study of the Safety and Antitumor Activity of the Hypoxia-Activated Prodrug TH-302 in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma". Journal of Clinical Oncology. 32 (29): 3299–306. doi:10.1200/JCO.2013.54.3660. PMID 25185097.
  8. ↑ Wilson, William R.; Hay, Michael P. (2011). "Targeting hypoxia in cancer therapy". Nature Reviews Cancer. 11 (6): 393–410. doi:10.1038/nrc3064. PMID 21606941.
  9. ↑ 9.0 9.1 9.2 Hu, James S; Skeate, Joseph G; Kast, Wijbe Martin (2014). "Immunotherapy in sarcoma: A brief review". Sarcoma Research International. 1 (1): id1003.
  10. ↑ 10.0 10.1 10.2 10.3 Wilky, Breelyn; Goldberg, John M. (April 14, 2014). "Immunotherapy in sarcoma: A new frontier". Discovery Medicine. 17 (94): 201–6.
  11. ↑ 11.0 11.1 Pedrazzoli, Paolo; Secondino, Simona; Perfetti, Vittorio; Comoli, Patrizia; Montagna, Daniela (2011). "Immunotherapeutic Intervention against Sarcomas". Journal of Cancer. 2: 350–6. doi:10.7150/jca.2.350. PMC 3119402. PMID 21716856.
  12. ↑ Ratnavelu, Kananathan; Subramani, Baskar; Pullai, Chithra Ramanathan; Krishnan, Kohila; Sugadan, Sheela Devi; Rao, Manjunath Sadananda; Veerakumarasivam, Abhi; Deng, Xuewen; Hiroshi, Terunuma (2013). "Autologous immune enhancement therapy against an advanced epithelioid sarcoma: A case report". Oncology Letters. 5 (5): 1457–1460. doi:10.3892/ol.2013.1247. PMC 3678875. PMID 23761810.
  13. ↑ Ciardiello, F; Troiani, T; Bianco, R; Orditura, M; Morgillo, F; Martinelli, E; Morelli, MP; Cascone, T; Tortora, G (2006). "Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy". Annals of Oncology. 17 (Suppl 7): vii109–14. doi:10.1093/annonc/mdl962. PMID 16760272.
  14. ↑ Hirata, Akira; Ogawa, Soh-ichiro; Kometani, Takuro; Kuwano, Takashi; Naito, Seiji; Kuwano, Michihiko; Ono, Mayumi (2002). "ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase". Cancer Research. 62 (9): 2554–60. PMID 11980649.
  15. ↑ Carmeliet, Peter; Dor, Yuval; Herbert, Jean-Marc; Fukumura, Dai; Brusselmans, Koen; Dewerchin, Mieke; Neeman, Michal; Bono, Françoise; Abramovitch, Rinat; Maxwell, Patrick; Koch, Cameron J.; Ratcliffe, Peter; Moons, Lieve; Jain, Rakesh K.; Collen, Désiré; Keshet, Eli (1998). "Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis". Nature. 394 (6692): 485–90. doi:10.1038/28867. PMID 9697772.
  16. ↑ 16.0 16.1 16.2 Samson, Kurt (2014). "LEE011 CDK Inhibitor Showing Early Promise in Drug-Resistant Cancers". Oncology Times. 36 (3): 39–40. doi:10.1097/01.COT.0000444043.33304.c1.
  17. ↑ Kim, S.; Loo, A.; Chopra, R.; Caponigro, G.; Huang, A.; Vora, S.; Parasuraman, S.; Howard, S.; Keen, N.; Sellers, W.; Brain, C. (2014). "Abstract PR02: LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6- Reactivating Rb in cancer". Molecular Cancer Therapeutics. 12 (11_Supplement): PR02. doi:10.1158/1535-7163.TARG-13-PR02.
  18. ↑ Geoerger, B.; Bourdeaut, F.; Dubois, S.G.; Dewire, M.D.; Marabelle, A.; Pearson, A.D.; Modak, S.; Kan, R.; Matano, A.; Bhansali, S.G.; Parasuraman, S.; Chi, S.N. (2014). "455P PHASE I STUDY OF LEE011 (CDK4/6 INHIBITOR) IN PATIENTS WITH MALIGNANT RHABDOID TUMORS, NEUROBLASTOMA, AND CYCLIN D–CDK4/6 PATHWAY-ACTIVATED TUMORS". Annals of Oncology. 25 (suppl 4): iv151–2. doi:10.1093/annonc/mdu331.15 (inactive October 6, 2015). line feed character in |title= at position 5 (help)
  19. ↑ Sosman, Jeffrey Alan; Kittaneh, Muaiad; Lolkema, Martijn P. J. K.; Postow, Michael Andrew; Schwartz, Gary; Franklin, Catherine; Matano, Alessandro; Bhansali, Suraj; Parasuraman, Sudha; Kim, Kevin (2014). "A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity". Journal of Clinical Oncology. 32 (15 Suppl): 9009.
  20. ↑ Wood, Andrew C.; Krytska, Kateryna; Ryles, Hannah; Sano, Renata; Li, Nanxin; King, Frederick; Smith, Timothy; Tuntland, Tove; Kim, Sunkyu; Caponigro, Giordano; He, You Qun; Jennifer, Harris; Mosse, Yael (2014). "Abstract 1000: Combination CDK4/6 and ALK inhibition demonstrates on-target synergy against neuroblastoma". Cancer Research. 74 (19 Supplement): 1000. doi:10.1158/1538-7445.AM2014-1000.
  21. ↑ Demetri, GD (2002). "Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571)". European Journal of Cancer. 38 (Suppl 5): S52–9. doi:10.1016/s0959-8049(02)80603-7. PMID 12528773.
  22. ↑ 22.0 22.1 22.2 22.3 Arora, Amit; Scholar, Eric M. (2005). "Role of Tyrosine Kinase Inhibitors in Cancer Therapy". Journal of Pharmacology and Experimental Therapeutics. 315 (3): 971–9. doi:10.1124/jpet.105.084145. PMID 16002463.
  23. ↑ Lengyel, Ernst; Sawada, Kenjiro; Salgia, Ravi (2007). "Tyrosine Kinase Mutations in Human Cancer". Current Molecular Medicine. 7 (1): 77–84. doi:10.2174/156652407779940486. PMID 17311534.
  24. ↑ 24.0 24.1 24.2 24.3 Gerecitano, John (2014). "SINE (selective inhibitor of nuclear export) – translational science in a new class of anti-cancer agents". Journal of Hematology & Oncology. 7: 67. doi:10.1186/s13045-014-0067-3. PMC 4197302. PMID 25281264.
  25. ↑ Sakakibara, K.; Saito, N.; Sato, T.; Suzuki, A.; Hasegawa, Y.; Friedman, J. M.; Kufe, D. W.; VonHoff, D. D.; Iwami, T.; Kawabe, T. (2011). "CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity". Blood. 118 (14): 3922–31. doi:10.1182/blood-2011-01-333138. PMID 21841164.
  26. ↑ 26.0 26.1 Hill, Richard; Cautain, Bastien; de Pedro, Nuria; Link, Wolfgang (2014). "Targeting nucleocytoplasmic transport in cancer therapy". Oncotarget. 5 (1): 11–28. doi:10.18632/oncotarget.1457. PMC 3960186. PMID 24429466.
  27. ↑ 27.0 27.1 Gravina, Giovanni; Senapedis, William; McCauley, Dilara; Baloglu, Erkan; Shacham, Sharon; Festuccia, Claudio (2014). "Nucleo-cytoplasmic transport as a therapeutic target of cancer". Journal of Hematology & Oncology. 7: 85. doi:10.1186/s13045-014-0085-1. PMC 4272779. PMID 25476752.
  28. ↑ Turner, Joel G.; Dawson, Jana; Cubitt, Christopher L.; Baz, Rachid; Sullivan, Daniel M. (2014). "Inhibition of CRM1-dependent nuclear export sensitizes malignant cells to cytotoxic and targeted agents". Seminars in Cancer Biology. 27: 62–73. doi:10.1016/j.semcancer.2014.03.001. PMC 4108511. PMID 24631834.
  29. ↑ Craig, Errol; Zhang, Zhi‐Kai; Davies, Kelvin P.; Kalpana, Ganjam V. (2002). "A masked NES in INI1/hSNF5 mediates hCRM1-dependent nuclear export: implications for tumorigenesis". The EMBO Journal. 21 (1–2): 31–42. doi:10.1093/emboj/21.1.31. PMC 125819. PMID 11782423.
  30. ↑ 30.0 30.1 30.2 Pol, Jonathan G; Rességuier, Julien; Lichty, Brian D (2012). "Oncolytic viruses: a step into cancer immunotherapy". Virus Adaptation and Treatment. 4: 1–21. doi:10.2147/VAAT.S12980.
  31. ↑ 31.0 31.1 31.2 31.3 Hemminki, Akseli (2014). "Oncolytic Immunotherapy: Where Are We Clinically?". Scientifica. 2014: 862925. doi:10.1155/2014/862925. PMC 3914551. PMID 24551478.
  32. ↑ Bramante, Simona; Koski, Anniina; Kipar, Anja; Diaconu, Iulia; Liikanen, Ilkka; Hemminki, Otto; Vassilev, Lotta; Parviainen, Suvi; Cerullo, Vincenzo; Pesonen, Saila K; Oksanen, Minna; Heiskanen, Raita; Rouvinen-Lagerström, Noora; Merisalo-Soikkeli, Maiju; Hakonen, Tiina; Joensuu, Timo; Kanerva, Anna; Pesonen, Sari; Hemminki, Akseli (2014). "Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans". International Journal of Cancer. 135 (3): 720–30. doi:10.1002/ijc.28696. PMID 24374597.
  33. ↑ 33.0 33.1 Siurala, Mikko; Bramante, Simona; Vassilev, Lotta; Hirvinen, Mari; Parviainen, Suvi; Tähtinen, Siri; Guse, Kilian; Cerullo, Vincenzo; Kanerva, Anna; Kipar, Anja; Vähä-Koskela, Markus; Hemminki, Akseli (2015). "Oncolytic adenovirus and doxorubicin-based chemotherapy results in synergistic antitumor activity against soft-tissue sarcoma". International Journal of Cancer. 136 (4): 945–54. doi:10.1002/ijc.29048. PMID 24975392.
  34. ↑ 34.0 34.1 Li, Gui-Dong; Kawashima, Hiroyuki; Ogose, Akira; Ariizumi, Takashi; Hotta, Tetsuo; Kuwano, Ryozo; Urata, Yasuo; Fujiwara, Toshiyoshi; Endo, Naoto (2013). "Telomelysin shows potent antitumor activity through apoptotic and non-apoptotic cell death in soft tissue sarcoma cells". Cancer Science. 104 (9): 1178–88. doi:10.1111/cas.12208. PMID 23718223.


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