BackgroundManipulation of immune checkpoints such as CTLA4 or PD-1 with targeted antibodies has recently emerged as an effective anticancer strategy in multiple malignancies. Sarcomas are a heterogeneous group of diseases in need of more effective treatments. Different subtypes of soft tissue and bone sarcomas have been shown to express PD-1 ligand.MethodsWe retrospectively analyzed a cohort of patients (pts) with relapsed metastatic/unresectable sarcomas, who were treated with nivolumab provided under a patient assistance program from the manufacturer. Pts underwent CT or PET/CT imaging at baseline and after at least four doses of nivolumab; RECIST 1.1 criteria were used for response assessment.ResultsTwenty-eight pts with soft tissue (STS, N = 24) or bone sarcoma (N = 4), received IV nivolumab 3 mg/kg every 2 weeks from July 2015. Median age was 57 (24–78), male:female ratio was 14:14; the median number of nivolumab cycles was eight. Eighteen pts concomitantly received pazopanib at 400–800 mg daily. The most common side effect was grade 1–2 LFT elevations; grade 3–4 toxicity occurred in five patients (colitis, LFT elevations, pneumonitis). Twenty-four pts received at least four cycles. We observed three partial responses: one dedifferentiated chondrosarcoma, one epithelioid sarcoma and one maxillary osteosarcoma (last two patients on pazopanib); nine patients had stable disease including three leiomyosarcomas; 12 patients had progression of disease including 4 leiomyosarcoma. Clinical benefit (response + stability) was observed in 50% of the evaluable patients.ConclusionsThese data provide a rationale for further exploring the efficacy of nivolumab and other checkpoint inhibitors in soft tissue and bone sarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13569-016-0064-0) contains supplementary material, which is available to authorized users.
IntroductionBcl-2 and related proteins are key regulators of apoptosis that are expressed in solid tumors and hematologic malignancies. 1 Bcl-2 is known to be constitutively overexpressed in approximately 80% of follicular lymphomas and 20% of diffuse B-cell lymphomas as a result of the t(14;18) translocation and gene amplification, respectively. 2,3 Overexpression of antiapoptotic family members is associated with inhibition of apoptosis and chemotherapy resistance, resulting in lower clinical response rates and shortened survivals. [4][5][6][7][8][9] Targeting Bcl-2 family members offers new opportunities to address these survival pathways directly. One important benefit of these drugs relates to their ability to lower the threshold required to induce apoptosis, making them potentially complimentary with conventional chemotherapy approaches.AT-101, a derivative of the natural product gossypol, is a BH3 mimetic capable of binding to Bcl-2, Bcl-X L , and Mcl-1, attenuating their antiapoptotic influence. 10 Gossypol is a natural compound extracted from cottonseeds (Gossypium sp), which was initially used as an antifertility agent 11 and subsequently as a cytotoxic agent. [12][13][14][15][16][17][18][19][20] In the late 1980s, it was discovered that (Ϫ)-gossypol enantiomer exhibited the most potent anticancer activity compared with the racemic mixture or the (ϩ)-gossypol enantiomer. The 3D solution structure of small molecules including (Ϫ)-gossypol in complex with Bcl-X L revealed several crucial interactions accounting for the binding specificity of the negative enantiomer. Given the importance of Bcl-2 overexpression in many types of lymphomas, we investigated the in vitro and in vivo antitumor activity of AT-101 alone and in combination with different cytotoxic and biologic agents. The major objective of these studies was to define the best strategy for combining AT-101 with other agents based upon an understanding of its biologic effects on the cell. Methods Cells and cell linesRL is an Epstein-Barr virus (EBV)-negative diffuse large B-cell lymphoma (DLBCL) line harboring the t(14;18) translocation; H9 is a cutaneous T-cell lymphoma (CTCL) line obtained from ATCC (Manassas, VA); SKI is a diffuse large B-cell lymphoma line 21,22 ; HBL-2 and Granta are mantle cell lymphoma lines and both stain positive for Bcl-2 23,24 ; JJN-3 is a multiple myeloma cell line. 25 All cell lines were grown as previously described. 26 MaterialsAll reagents for Western blotting were obtained from Bio-Rad Laboratories (Hercules, CA) and Pierce Biotechnology (Rockford, IL); dimethyl sulfoxide (DMSO) was obtained from Sigma-Aldrich (St Louis, MO). Drugs were obtained as follows: AT-101, from Ascenta Therapeutics (Malvern, PA); Submitted December 22, 2007; accepted February 13, 2008. Prepublished online as Blood First Edition paper, February 21, 2008 DOI 10.1182 DOI 10. /blood-2007 An Inside Blood analysis of this article appears at the front of this issue.The publication costs of this article were defrayed in part by page charge payme...
IMPORTANCE Alveolar soft-part sarcoma (ASPS) is a rare, translocation-driven sarcoma of the soft tissues. Alveolar soft-part sarcoma often affects young adults and is characterized by indolent behavior but early evidence of metastatic spread. After recognition of ASPS as a specific entity in 1952, retrospective data indicated prolonged survival in patients with metastases, despite inherent resistance to conventional doxorubicin-based chemotherapy. Tyrosine kinase inhibitors and immune checkpoint inhibitors have provided unexpected new treatment strategies for ASPS.OBSERVATIONS This review includes articles published between 1952 and March 1, 2018. With the introduction of new molecular diagnostic tools and therapies, the distinctive features of ASPS have become more evident. The identification and better understanding of molecular pathways activated by the characteristic t(X;17)(p11;q25) translocation and its correspondent chimeric ASPSCR1-transcription factor E3 (TFE3) fusion protein open new paths to drug development. The associations of TFE3 and facilitation of an immunosuppressive microenvironment provide a rationale for exploring treatments that affect the balance between T-effector cells and T-regulatory cells. Tyrosine kinase inhibitors, such as sunitinib, cediranib, and pazopanib, show activity with either tumor responses or disease stabilization in more than 50% of the cases. Given the association of new agents with patient outcomes, it is too early to say whether metastatic ASPS should still be considered incurable in all patients. CONCLUSIONS AND RELEVANCEThe biologic outcomes of the canonical genomic event in ASPS remain under investigation; a better understanding of the tumor microenvironment and the multiple pathways activated in this sarcoma, including unusual bioenergetics, MET signaling, and angiogenesis, should lead to more rational therapy. Basket trials and related prospective studies focusing on the intersection of specific signaling pathways and diseases with unique genomic features, such as ASPS, will provide an understanding of new options for care.
Purpose: Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier (RFC-1) and folyl-polyglutamyl synthase. Based on the PROPEL data, pralatrexate was the first drug approved for patients with relapsed and refractory peripheral T-cell lymphoma. Bortezomib is a proteasome inhibitor that has shown some activity in patients with T-cell lymphoma.Experimental Design: Assays for cytotoxicity including mathematical analysis for synergism, flow cytometry, immunoblotting, and a xenograft severe combined immunodeficient-beige mouse model were used to explore the in vitro and in vivo activities of pralatrexate alone and in combination with bortezomib in T-cell lymphoid malignancies.Results: In vitro, pralatrexate and bortezomib exhibited concentration-and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines. Pralatrexate showed synergism when combined with bortezomib in all cell lines studied. Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel. Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents. Western blot assays for proteins involved in broad growth and survival pathways showed that p27, NOXA, HH3, and RFC-1 were all significantly modulated by the combination. In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of pralatrexate to bortezomib enhanced efficacy compared with either drug alone.Conclusion: Collectively, these data suggest that pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of T-cell malignancies. Clin Cancer Res; 16(14); 3648-58. ©2010 AACR.
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