Although Kaposi's sarcoma (KS), the most common AIDS-defining malignancy worldwide,1,2 can be treated with antiretroviral therapy (ART) alone or with chemotherapy added,3–5 responses are often incomplete. Cytotoxic chemotherapy may induce acute and chronic adverse events and pharmacokinetic interactions with ART, and access to chemotherapy is limited in high-incidence, low-resource regions, especially sub-Saharan Africa.6,7 Thus, alternative treatments are needed.
Vascular endothelial growth factor (VEGF) is highly overexpressed in KS tumors and enhances KS-associated herpesvirus (KSHV) entry and KS gene expression within target cells.8,9 In laboratory studies, inhibiting VEGF expression or its signaling pathways results in tumor growth inhibition.10–14 KSHV-encoded proteins promote vascular endothelial reprogramming and immortalization through upregulation of VEGF and VEGF receptors (VEGFr).15,16 In addition, tumor hypoxia induces p53-mediated apoptosis and HIF-1α, further promoting VEGF production.17 HIF-1α and hypoxemic responses are additionally modulated directly by KSHV, and hypoxia further promotes lytic KSHV replication.18–21
PTC299 (PTC Therapeutics Inc., South Plainfield, NJ), an orally bioavailable VEGF inhibitor, acts through posttranscriptional regulation of VEGF mRNA under conditions of cellular stress. Transcriptional regulation of VEGF in normal endothelial cells occurs mainly through cap-dependent translation of its mRNA. In contrast, cellular stress and hypoxemia augment transcription of VEGF in a cap-independent fashion.22–24 Because PTC299 targets cap-independent pathways of mRNA translation that predominate during stress such as hypoxia and oncogenic transformation, VEGF production in normal endothelium is spared, potentially avoiding undesirable off-target effects of generalized VEGF blockade observed with other VEGF and VEGFr tyrosine kinase inhibitors (TKIs). PTC299 activity was demonstrated in a variety of tumor cell lines and mouse xenograft-tumor models and was safe and well tolerated in several phase I clinical trials.25–28
These considerations led the AIDS Malignancy Consortium to evaluate the safety, dosing, antitumor activity, and pharmacokinetics of PTC299 in patients with HIV-associated KS, and to describe its effects on VEGF expression and KSHV replication.
Eligible participants were HIV-infected adults with biopsy-proven KS not requiring urgent systemic chemotherapy for symptomatic visceral disease. Participants receiving ART were required to be on a stable regimen ≥12 weeks without improvement in KS during that time, not pregnant or breastfeeding, and to have received no KS treatment within 1 month. Exclusions included Karnofsky score <60, life expectancy <3 months, history of bleeding or clotting diathesis, severe hepatic or renal dysfunction, or other active serious medical conditions.
After providing informed consent, 3 participants were sequentially enrolled into each of 3 oral dosage levels, 40 mg twice daily (BID), 80 mg BID, and 100 mg BID, once the preceding dose had been administered without dose-limiting toxicities for 1 cycle. Eight additional participants then received 100 mg BID. PTC299 was supplied as 20 mg capsules. A plan to estimate the maximum tolerated dosage was not performed because the sponsor suspended enrollment because of change in drug formulation. Each drug cycle lasted 28 days. KS response was assessed every 28 days as previously described,29,30 and categorized as complete (CR), partial (PR), stable (SD) or progression (PD). Participants were considered evaluable for response if they completed 1 cycle of PTC299. Participants without CR or PR were removed from study after 6 cycles; treatment was likewise discontinued if KS progressed on therapy or dose limiting toxicities occurred. Participants were continued on therapy for an additional 2 cycles after CR, or up to 12 cycles for PR.
Biopsies of nonindicator KS lesions were performed at baseline and during week 4, cycle 1, and evaluated for changes in expression of viral, angiogenesis, and proliferation markers (see Supplemental Material, http://links.lww.com/QAI/A780).
KSHV DNA was quantified in plasma at baseline, cycles 2 and 5, and treatment discontinuation, using competitive DNA PCR.31 Whole blood CD4+ T-cell counts and plasma HIV RNA levels were determined at these same time points.
VEGF-A and IL-6 levels were quantified by enzyme-linked immunosorbent assay (Quest Laboratories, San Juan Capistrano, CA) in serum and plasma on day 1 of cycles 1–6, on cycle 1, day 15, and at treatment discontinuation.
Serial blood samples for pharmacokinetic analysis were collected immediately preceding and at 1, 2, 3, 4, 5, 6, and 8 hours after the morning administration of PTC299 on cycle 1, days 1 and 28. Additional trough samples were obtained on cycle 1, day 15 and cycle 2, day 28. Samples were analyzed and pharmacokinetic parameters estimated as described (see Supplemental Material, http://links.lww.com/QAI/A780).
Descriptive statistics were used to summarize adverse events and response rates.
Effects of PTC299 on serum and plasma VEGF, VEGFR, and cytokine profiles were evaluated comparing pretreatment values with day 28 and with the lowest value subsequent to day 28, and differences tested with Wilcoxon signed-rank tests. Methods for analyzing other correlative laboratory endpoints are described in the Supplemental Materials (http://links.lww.com/QAI/A780).
Seventeen volunteers were enrolled: 3 at 40 mg BID, 3 at 80 mg BID, and 11 at 100 mg BID. Baseline characteristics, including extent of KS, ART regimen, HIV parameters, and previous KS therapy are described in Table 1, as are details of study treatment.
Five participants completed therapy per protocol, 6 terminated study treatment of KS progression, and 4 voluntarily withdrew after a median of 3 cycles. One patient died and 1 withdrew from study before the first response evaluation. PR was documented in 3 participants (18%), lasting for 2–4 months, respectively, at doses of 40 mg BID (n = 1) and 100 mg BID (n = 2). Eleven participants showed SD lasting a median of 3 months (interquartile range 2–6.5). PD ultimately occurred in 6 participants, of whom 5 initially had either PR or SD.
Common adverse events included nausea (41%), vomiting (18%), diarrhea (24%), limb pain (47%), and fatigue (29%); >90% of events were grade 1 or 2. Limb pain, fatigue, and peripheral edema were prevalent at baseline and consistent with the primary disease. Hyperglycemia (29%), dyslipidemia (53%), elevated creatinine (18%), and proteinuria (18%) were the most frequent laboratory abnormalities. Three participants (18%), all receiving atazanavir, had elevated bilirubin. All participants with elevated creatinine and/or proteinuria received concurrent tenofovir. Serious adverse events were reported in 3 participants: 1 grade 3 nephrolithiasis, considered unlikely related to study drug; 1 grade 3 myalgia at the 100 mg/dose level, considered probably PTC299-related; and 1 death. The death was officially ascribed to hypertensive cardiovascular disease and reported as possibly study drug-related, although autopsy revealed detectable serum levels of several illicit and prescription opiates and sedatives; precise cause of death is therefore uncertain.
Pharmacokinetic analysis was available for 15 patients. A post hoc analysis categorizing participants on whether the ART regimen was known to induce CYP2C19 (ritonavir) or inhibit CYP2C19 (efavirenz)32 showed no statistically significant alterations in pharmacokinetics of the parent compound, but significant alterations in exposure to the less-active metabolite, des-methyl PTC299 (see Supplemental Material, http://links.lww.com/QAI/A780).33 There was no correlation between treatment response and PTC299 or metabolite exposure (P > 0.05).
Effects of PTC299 on Biologic Markers
Day 1, cycle 1 levels of serum VEGF were significantly higher than levels at all later time points (Fig. 1); plasma VEGF showed a less sustained decrease that was significant only at intermediate time points. No changes were observed in serum or plasma IL-6.
There were no significant treatment-associated changes in KSHV viral loads, absolute and percent CD4, or immunohistochemical expression of VEGF, VEGFr, phospho-Akt, p53, HIF-1α, or Ki-67, or viral gene expression or cellular gene transcription in tumor biopsies.
Recognition of the essential role of VEGF in KS development has prompted evaluation of several VEGF inhibitors in AIDS-associated KS. This study evaluated PTC299, a novel, orally bioavailable small molecule that inhibits VEGF protein production by preventing translation of pathological VEGF. Because the study was halted early, we were unable to define the maximum tolerated dosage in this population, but doses administered were similar to those tested in other phase I and II studies. Those trials and ours demonstrated a pharmacokinetic profile for PTC299 consistent with maintenance of drug levels well above those required for efficacy in preclinical models.
Participants were allocated to PTC299 dosage levels without respect to the concurrent antiretroviral regimen. We observed no significant variation between participants receiving CYP2C19 inducers and inhibitors in the pharmacokinetics of the parent drug, nor correlation of treatment response with drug and metabolite exposure, although metabolite exposure and metabolite:parent drug ratio differed significantly between these 2 groups. Without stratified dosage assignments, such as those used in a subsequent AIDS Malignancy Consortium trial of sunitinib,34 we were unable to correlate adverse events by ART regimen effects on CYP2C19.
We did not observe many of the medically significant side effects of VEGF inhibitors and TKIs, such as bleeding, hypertension, and renal vascular injury.35,36 Mild proteinuria was limited to persons receiving tenofovir and/or atazanavir, both known to cause renal tubulopathies37 and all persons with elevated bilirubin levels were receiving atazanivir.38 Fewer adverse events were observed than for other classes of VEGF inhibitors/TKIs, suggesting that drugs inhibiting VEGF by targeting tumor-specific mRNA rather than general kinase activity may be less likely to induce off-target effects. The short duration of PTC299 administration in some participants may, however, have precluded observation of potential adverse events.
Although we could not evaluate the planned dosage range of PTC299, moderate serum VEGF inhibition was achieved, although, only modest effects on KS growth, consistent with results from other VEGF inhibitors. Many participants had previously received multiple KS treatments, but we did not note a pattern of response with respect to previous receipt of agents with anti-VEGF activity. Other studies of VEGF inhibitors in KS reported a 30% response rate for bevacizumab, 20% for sorafenib, and no better than SD for sunitunib.34,39–41 As such, this study highlights a persistent question in the search for improved therapies for KS and many soft tissue sarcomas (STS), which similarly overexpress VEGF and its receptors.42 It is unclear why, despite the apparent reliance of many such tumors on VEGF overproduction, VEGF inhibitors have not proven highly efficacious in these tumors. Five VEGF inhibitors have been studied in other STS, of which 4 received approval for this indication. However, single-agent PR rates were only 14% for sorafenib,43 17% for bevacizumab,44 6% for pazopanib,45 and metabolic PR in 47% of patients receiving sunitinib for varied STS.46 Despite PTC299 activity in multiple preclinical in vivo sarcoma models,33 and a statistically significant decrease in serum VEGF levels in this trial, the response rate of 20% was similar to rates for other TKIs, but inferior to standard-of-care chemotherapy.
One reason that single-point blockade of the VEGF pathway may be insufficient to cause tumor regression, particularly in AIDS-related KS, is redundancy in the human VEGF pathway, which KSHV reinforces at several points.40 In addition, whereas VEGF is necessary for proliferation, it may not be necessary for tumor survival. This is similar to the mTOR pathway, an upstream regulator of VEGF and IL-6 expression.47–50 Viral IL-6 and KSHV-mediated upregulation of HIF-1α and VEGFrs may reinforce this autocrine-paracrine loop, such that single-point blockade of the VEGF pathway is easily circumvented. Virus-tumor interactions, allowing upregulation of alternate pathways, may explain why objective responses to single-agent VEGF inhibitors have been modest. Finally, because pharmacologic growth factor depletion is seldom complete, the typical outcome of single-agent therapy in preclinical studies is growth arrest, translating to no better than SD in most patients.
Given the limited therapeutic results of VEGF monotherapy, a logical next step may be to combine mechanistically distinct VEGF inhibitors51 or VEGF inhibitors with agents that target either tumor or virus. A current example is an ongoing trial of bevacizumab with liposomal doxorubicin (NCT00923936). In addition, nucleoside analog inhibitors of viral DNA polymerase with direct gamma herpesvirus activity, despite little anti-KS efficacy as single agents,52,53 may provide adjuvant effects against virally mediated paracrine stimulation to remove redundancy in the VEGF pathway. Furthermore, several HIV protease inhibitors have off-target effects on pathways regulating tumor growth, including Akt, NF-κB, and the 20S proteasome.54,55 Of particular interest is nelfinavir, which downregulates HIF-1α and VEGF, and has direct antiherpesvirus activity.56,57
The authors thank the members of the AMC-059 Study Team [David Aboulafia, Virginia Mason Medical Center, Seattle, WA; Robert Baiocchi, Ohio State Medical Center, Columbus, OH; Elizabeth Y. Chiao, Baylor College of Medicine, Houston, TX; Bruce J. Dezube, Beth Israel Deaconess Hospital, Boston, MA; Ronald T. Mitsuyasu, University of California Los Angeles (UCLA) and UCLA Clinical AIDS Research and Education (CARE) Center, Los Angeles, CA; Erin Gourley Reid, University of California San Diego, Moores Cancer Center, LA Jolla, CA; Bruce Shiramizu, University of Hawaii John A. Burns School of Medicine, Honolulu, HI; Joseph A. Sparano, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Anil Tulpule, University of Southern California Keck School of Medicine, Los Angeles, CA] for their recruitment and management of the study participants; Anthony Eason and Veenadhari Chavakula (Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC) for performing immunohistochemistry and gene expression analyses; PTC Therapeutics for their provision of PTC299 and support for measurements of plasma drug level and serum and plasma cytokines; Julia Lynne, EMMES Corporation, Rockville, MD for her assistance in protocol development; and the study participants for taking part in this trial.
1. Whitby D, Howard MR, Tenant-Flowers M, et al.. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet. 1995;346:799–802.
2. Schalling M, Ekman M, Kaaya EE, et al.. A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nat Med 1995;1:707–708.
3. Cianfrocca M, Lee S, Von Roenn J, et al.. Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma: evidence of symptom palliation from chemotherapy. Cancer. 2010;116:3969–3977.
4. Cooley T, Henry D, Tonda M, et al.. A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma. Oncologist. 2007;12:114–123.
5. Mosam A, Shaik F, Uldrick TS, et al.. A randomized controlled trial of highly active antiretroviral therapy versus highly active antiretroviral therapy and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa. J Acquir Immune Defic Syndr 2012;60:150–157.
6. Adebamowo CA, Casper C, Bhatia K, et al.. Challenges in the detection, prevention, and treatment of HIV-associated malignancies in low- and middle-income countries in Africa. J Acquir Immune Defic Syndr 2014;67(suppl 1):S17–S26.
7. Krown SE, Borok MZ, Campbell TB, et al.. Stage-stratified approach to AIDS-related Kaposi's sarcoma: implications for resource-limited environments. J Clin Oncol 2014;32:2512–2513.
8. Sivakumar R, Sharma-Walia N, Raghu H, et al.. Kaposi's sarcoma-associated herpesvirus induces sustained levels of vascular endothelial growth factors A and C early during in vitro infection of human microvascular dermal endothelial cells: biological implications. J Virol 2008;82:1759–1776.
9. Hamden KE, Whitman AG, Ford PW, et al.. Raf and VEGF: emerging therapeutic targets in Kaposi's sarcoma-associated herpesvirus infection and angiogenesis in hematopoietic and nonhematopoietic tumors. Leukemia. 2005;19:18–26.
10. Bais C, Van Geelen A, Eroles P, et al.. Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/KDR. Cancer Cell 2003;3:131–143.
11. Mutlu AD, Cavallin LE, Vincent L, et al.. In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma. Cancer Cell 2007;11:245–258.
12. Samaniego F, Markham PD, Gendelman R, et al.. Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi's sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular permeability and KS lesion development. Am J Pathol 1998;152:1433–1443.
13. Wang L, Dittmer DP, Tomlinson CC, et al.. Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus. Cancer Res 2006;66:3658–3666.
14. Carroll PA, Brazeau E, Lagunoff M. Kaposi's sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation. Virology. 2004;328:7–18.
15. Wang HW, Trotter MW, Lagos D, et al.. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 2004;36:687–693.
16. Hong YK, Foreman K, Shin JW, et al.. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 2004;36:683–685.
17. Catrina SB, Botusan IR, Rantanen A, et al.. Hypoxia-inducible factor-1α and hypoxia-inducible factor-2α are expressed in Kaposi sarcoma and modulated by insulin-like growth factor-I. Clin Cancer Res 2006;12:4506–4514.
18. Carroll PA, Kenerson HL, Yeung RS, et al.. Latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells activates hypoxia-induced factors. J Virol 2006;80:10802–10812.
19. Davis DA, Rinderknecht AS, Zoeteweij JP, et al.. Hypoxia induces lytic replication of Kaposi sarcoma–associated herpesvirus. Blood. 2001;97:3244–3250.
20. Sodhi A, Chaisuparat R, Hu J, et al.. The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1α. Cancer Res 2000;60:4873–4880.
21. Haque M, Davis DA, Wang V, et al.. Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) contains hypoxia response elements: relevance to lytic induction by hypoxia. J Virol 2003;77:6761–6768.
22. Huez I, Créancier L, Audigier S, et al.. Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol Cell Biol 1998;18:6178–6190.
23. Stein I, Itin A, Einat P, et al.. Translation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia. Mol Cell Biol 1998;18:3112–3119.
24. Levy AP, Levy NS, Goldberg MA. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 1996;271:2746–2753.
25. Packer RJ, Rood BR, Turner DC, et al.. Phase I and pharmacokinetic trial of PTC299 in pediatric patients with refractory or recurrent central nervous system tumors: a PBTC study. J Neurooncol 2015;121:217–224.
26. Fong B, Barkhoudarian G, Pezeshkian P, et al.. The molecular biology and novel treatments of vestibular schwannomas. J Neurosurg 2011;115:906–914.
27. Knight D, Tiersten A, Miao H, et al.. PTC299, a novel regulator of tumor VEGF expression, is well tolerated and achieves target plasma concentrations: dose-ranging results of a phase 1b study in women with metastatic breast cancer. Cancer Res 2009;69(24 suppl):6092.
28. Hirawat S, Elfring GL, Northcutt VJ, et al.. Phase 1 studies assessing the safety, PK, and VEGF-modulating effects of PTC299, a novel VEGF expression inhibitor. Paper presented at: ASCO Annual Meeting Proceedings; Chicago, Illinois, June 2–4, 2007.
29. Krown SE, Metroka C, Wernz J, et al.. Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1989;7:1201–1207.
30. Cianfrocca M, Cooley TP, Lee JY, et al.. Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: a phase I AIDS malignancy consortium study. J Clin Oncol 2002;20:153–159.
31. Lin L, Lee JY, Kaplan LD, et al.. Effects of chemotherapy in AIDS-associated non-Hodgkin's lymphoma on Kaposi's sarcoma herpesvirus DNA in blood. J Clin Oncol 2009;27:2496–2502.
32. Rudek MA, Flexner C, Ambinder RF. Use of antineoplastic agents in patients with cancer who have HIV/AIDS. Lancet Oncol 2011;12:905–912.
33. PTC Therapeutics, Inc. PTC 299 Investigator Brochure. Version 6. South Plainfield, New Jersey: PTC Theraputics, Inc; 2012.
34. Rudek MA, Moore PC, Mitsuyasu RT, et al.. A phase 1/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy in human immunodeficiency virus-positive patients with cancer: AIDS Malignancy Consortium trial AMC 061. Cancer. 2014;120:1194–1202.
35. Hayman SR, Leung N, Grande JP, et al.. VEGF inhibition, hypertension, and renal toxicity. Curr Oncol Rep 2012;14:285–294.
36. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007;96:1788–1795.
37. Post F. Adverse events: ART and the kidney: alterations in renal function and renal toxicity. J Int AIDS Soc 2014;17(4 suppl 3):19513.
38. Sanne I, Piliero P, Squires K, et al.. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 2003;32:18–29.
39. Uldrick TS, Wyvill K, Peer C, et al.. Phase I and pharmacokinetic study of sorafenib in Kaposi sarcoma. J Clin Oncol 2013;31(15):10588.
40. Uldrick TS, Wyvill K, Peer C, et al.. Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. J Clin Oncol 2012;30:1476–1483.
41. Noy A, von Roenn J, Politsmakher A, et al.. Fatal hepatorenal failure and thrombocytopenia with SU5416, a vascular endothelial growth factor Flk-1 receptor inhibitor, in AIDS-Kaposi's sarcoma. AIDS. 2007;21:113–115.
42. Park MS, Ravi V, Araujo DM. Inhibiting the VEGF-VEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma, and hemangiopericytoma/solitary fibrous tumor. Curr Opin Oncol 2010;22:351–355.
43. Maki RG, D'Adamo DR, Keohan ML, et al.. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol 2009;27:3133–3140.
44. Agulnik M, Yarber JL, Okuno SH, et al.. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol 2013;24:257–263.
45. van der Graaf WT, Blay JY, Chawla SP, et al.. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–1886.
46. George S, Merriam P, Maki RG, et al.. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol 2009;27:3154–3160.
47. Roy D, Sin SH, Lucas A, et al.. mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis. Cancer Res 2013;73:2235–2246.
48. Sodhi A, Chaisuparat R, Hu J, et al.. The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 2006;10:133–143.
49. Nichols LA, Adang LA, Kedes DH. Rapamycin blocks production of KSHV/HHV8: insights into the anti-tumor activity of an immunosuppressant drug. PLoS One. 2011. 6:e14535.
50. Chang HH, Ganem D. A unique herpesviral transcriptional program in KSHV-infected lymphatic endothelial cells leads to mTORC1 activation and rapamycin sensitivity. Cell Host Microbe 2013;13:429–440.
51. Azad NS, Posadas EM, Kwitkowski VE, et al.. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 2008;26:3709–3714.
52. Krown SE, Dittmer DP, Cesarman E. Pilot study of oral valganciclovir therapy in patients with classic Kaposi sarcoma. J Infect Dis 2011;203:1082–1086.
53. Little RF, Merced-Galindez F, Staskus K, et al.. A pilot study of cidofovir in patients with kaposi sarcoma. J Infect Dis 2003;187:149–153.
54. Gantt S, Casper C, Ambinder RF. Insights into the broad cellular effects of nelfinavir and the HIV protease inhibitors supporting their role in cancer treatment and prevention. Curr Opin Oncol 2013;25:495–502.
55. Bernstein WB, Dennis PA. Repositioning HIV protease inhibitors as cancer therapeutics. Curr Opin HIV AIDS 2008;3:666–675.
56. Gantt S, Carlsson J, Ikoma M, et al.. The HIV protease inhibitor nelfinavir inhibits Kaposi's sarcoma-associated herpesvirus replication in vitro. Antimicrob Agents Chemother 2011;55:2696–2703.
57. Gantt S, Gachelet E, Carlsson J, et al.. Nelfinavir impairs glycosylation of herpes simplex virus 1 envelope proteins and blocks virus maturation. Adv Virol 2015;2015:687162.