Prolonged Disease Stability With Trabectedin in a Heavily Pretreated Elderly Patient With Metastatic Leiomyosarcoma of the Thigh and Renal Failure: A Case Report and Review of the Literature

Leiomyosarcoma represents about 24% of all soft tissue sarcomas and can originate from retroperitoneum, uterus, or extremities. Adequate local control may be achieved with surgery and radiotherapy. In the presence of unresectable metastases either doxorubicin- or gemcitabine-based chemotherapy is the standard of treatment. Nevertheless, prognosis remains poor regardless of the selected chemotherapy regimen, and new effective therapeutic agents for patients with advanced leiomyosarcoma are needed. Trabectedin, a promising new DNA-damaging agent with a mechanism of action that is different from that of traditional alkylating agents, is approved in Europe for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents and in combination with pegylated liposomal doxorubicin (PLD) for the treatment of patients with relapsed platinum-sensitive ovarian cancer. We present a case of a 76-year-old patient with progressive metastatic lung lesions from a previously resected primary leiomyosarcoma of the thigh and moderate renal failure, who achieved 17 months of disease stability during third-line treatment with trabectedin. Trabectedin was not associated with any cumulative toxicity and was consistently well tolerated for a total of 22 treatment cycles. Current evidence on trabectedin is also presented.</jats:p

Alpha–fetoprotein elevation in NUT midline carcinoma: a case report

Abstract Background Nuclear protein in testis (NUT) midline carcinoma is a rarely diagnosed and potentially under-recognized type of squamous carcinoma that is considered one of the most aggressive human solid tumors. Alpha-fetoprotein elevation has been associated with chronic liver diseases and a limited number of cancers. In particular, in presence of a mediastinal mass in a young man, alpha-fetoprotein elevation is considered nearly pathognomonic of a non-seminoma germ-cell tumor. Case presentation A 22-year old man without any comorbidity was diagnosed with a large mediastinal mass with skeletal and lymph node metastases. The clinical picture was dominated by a life-threatening superior vena cava syndrome with elevated alpha-fetoprotein and lactate dehydrogenase that supported the diagnostic suspicion of mediastinal germ-cell tumor. However, a biopsy showed a poorly-differentiated and diffusely necrotic carcinoma. We eventually reached the diagnosis of the peculiar entity of NUT midline carcinoma, but the differential diagnosis was quite challenging also because alpha-fetoprotein is not reported as a marker of NUT midline carcinoma. Notably, alpha-fetoprotein levels correlated with disease course. Conclusions The life-threatening aggressiveness of NUT midline carcinoma mandates to reach the right diagnosis in the shortest possible time. In this regard, poorly differentiated carcinomas lacking glandular differentiation mandate testing for NUT expression by immunohistochemistry. Awareness of a potentially misleading tumor marker elevation can help to broaden the differential diagnosis and establish the most appropriate treatment

Abstract LB-213: The antitumor effect of trabectedin (TR) is potentiated by olaparib (OL) in preclinical models of bone and soft tissue sarcomas (STS).

Abstract Background. TR is a DNA-binding alkaloid approved in Europe for the treatment STS as second/third line therapy. TR interferes with gene transcription and nucleotide excision repair, inducing DNA double strand breaks (DSBs). There is a strong clinical interest to increase TR activity by combination with other anti-cancer drugs. PARP-1 inhibitors (PARPi) which disable DNA base-excision repair mechanism causing the accumulation of DSBs, look like a worth to explore TR therapeutic partners. Our preclinical studies were focused on the effects of the combination of TR with the PARPi (OL and veliparib). Methods: We explored DNA damage by comet assay and P-H2AX determination, PARP-1 activity by polyADPribosylation assay in a panel of 18 sarcoma cell lines, evaluating cell viability after 72h treatment with escalating doses of TR, PARPi, and their constant combination. Colony growth, cell cycle, apoptosis and DNA damage were evaluated. Antitumoral activity was checked after 4 weeks of treatment with 3 endovenous injection of TR once a week and OL intraperitoneally 5 days/week, and compared to control and single agents in bone (SJSA-1) and soft tissue sarcoma (DMR) xenografted NOD/SCID mice. TUNEL assay, P-H2AX, PCNA and CD31 immunohistochemistry was done on explanted xenografts. Results: We showed TR-induced DNA damage and PARP-1 activation in sarcoma sensitive cell line. The addition of PARPi completely blocked basal and TR-induced PARP-1 activation. DNA damage response and checkpoints (ATM, ATR, BRCA1, CHK1, CHK2, p53) were activated after single agents and combination treatment inducing cell cycle arrest in S/G2 phase. This block was released after 48h in single agent-treated cells but not in combination-treated cells leading to apoptotic cell death. Colony growth assay and viability tests revealed a strong synergism of the two drugs (Combination Index &amp;lt; 1, based on Chou-Talalay method). Different sarcoma histotypes displayed differences in sensitivity to both drugs and combination (Ewing's sarcoma the most sensitive&amp;gt; myxoid liposarcoma &amp;gt; leiomyosarcoma &amp;gt; osteosarcoma ≥ undifferentiated pleomorphic &amp;gt; fibrosarcoma). The antitumor effect of combined TR and OL was shown after in vivo treatment of SJSA-1 and DMR xenografted mice. A significant tumor volume reduction was observed if compared to both control and single agent and was attributed to increased DNA damage, apoptosis and reduced proliferation, but not to anti-angiogenic potentiation. In fact, a direct effect on tumor vasculature was shown in TR and combination treated group vs control. Conclusions: Our results validate the biological rationale to combine TR and PARPi in sarcoma and suggest exploring this pharmacological approach in the clinical setting. Citation Format: Ymera Pignochino, Federica Capozzi, Carmine Dell'aglio, Marco Basiricò, Lorenzo D'ambrosio, Danilo Galizia, Erica Palesandro, Maria Serena Benassi, Massimo Aglietta, Giovanni Grignani. The antitumor effect of trabectedin (TR) is potentiated by olaparib (OL) in preclinical models of bone and soft tissue sarcomas (STS). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-213. doi:10.1158/1538-7445.AM2013-LB-213</jats:p

Abstract 3709: PARP1 expression (PARP1expr) drives synergy between PARP1 inhibitors (PARP1-Is) and trabectedin (TR)

Abstract Purpose of study. An attractive strategy to improve antitumor treatments is to inflict cytotoxic DNA damage with chemotherapy, and then impede DNA repair by molecular targeting. TR is a new drug characterized by a peculiar mechanism of action: TR traps DNA repair machinery leading to DNA damage, particularly in BRCA1/2-deficient tumors. We speculated that TR might activate PARP1, a key player in DNA-repair, and that subsequent PARP1 inhibition perpetuates TR-induced DNA damage leading to cell death. Experimental procedures and results. We developed a preclinical platform of 31 cell lines from different histotypes to explore the potential synergy between TR and the PARP1-Is olaparib (OL) and veliparib. We demonstrated that, regardless of BRCA1/2 status, PARP1-Is significantly increased TR activity, but a 15-fold range of sensitivity to the combination was observed. OL was proven the best PARP-I to combine with TR, probably due to its PARP1 trapping activity. In selected experiments, whole-genome expression profiling and GSEA analysis comparing cells displaying high vs. low synergism of the combination (HS-C vs. LS-C) revealed that DDR, G2/M cell cycle checkpoint, and DNA repair pathways were mechanistically involved in TR+OL synergy. TR induced PARP1 activation in 3/6 cell lines and PARP1-Is completely blocked both basal and TR-induced PARP1 activation. OL enhanced DNA damage response in 6/6 cell lines, but unrepairable DNA fragmentation was obtained in cells with high PARP1expr only. In two independent cell panels TR+OL synergism was directly related to PARP1expr both at mRNA (Pearson score r: 0.70, p = 0.00079) and protein level (r: 0.71, p = 0.015). Silencing and overexpression experiments validated the functional role of PARP1expr in determining TR+OL synergism: in HS-C the downmodulation of PARP1expr reduced sensitivity to TR+OL while the overexpression of PARP1 in LS-C rose TR+OL activity to levels observed in HS-C. Subcutaneous, intravenous and orthotopic xenografts of one HS-C (DMR) and one LS-C (SJSA-1) in NOD/SCID mice revealed OL significantly increased antitumor and antimetastatic activity of TR in cells with high PARP1expr only. Finally, we demonstrated that basal PARP1expr PARP1 activation by other cytotoxics with a stronger PARP1 activation observed in cells with high vs. low PARP1expr, regardless of the considered drug. Conclusions. OL enhances and potentially broaden TR cytotoxicity. TR+OL combination is particularly attractive in tumors harboring high PARP1expr and specific DDR-R gene signatures that might become predictive biomarkers of response. Future clinical validation of TR+OL combination may extend the use of PARP1-Is beyond BRCA1/2 defective tumors. Indeed, the crucial role of PARP1expr is confirmed regardless of tumor histotype and BRCA1/2 status. Further studies of combination between PARP1-Is and other cytotoxics should consider basal PARP1expr and activation after drug exposure. Citation Format: Ymera Pignochino, Federica Capozzi, Lorenzo D’ambrosio, Carmine Dell’aglio, Marco Basiricò, Paola Boccone, Erica Palesandro, Loretta Gammaitoni, Dario Sangiolo, Maria Serena Benassi, Massimo Aglietta, Giovanni Grignani. PARP1 expression (PARP1expr) drives synergy between PARP1 inhibitors (PARP1-Is) and trabectedin (TR). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3709.</jats:p