Erica Palesandro

Complete Resolution of Life-Threatening Bleomycin-Induced Pneumonitis After Treatment With Imatinib Mesylate in a Patient With Hodgkin's Lymphoma: Hope for Severe Chemotherapy-Induced Toxicity?

Introduction Bleomycin-induced pneumonitis (BIP) is a scarcely manageable pulmonary toxicity that occurs in approximately 20% of patients who are affected with cancers that are treated with bleomycin-containing regimens. Generally, the clinical picture is extremely complicated and therapy is based on steroids. The overall response rate to such therapy is limited. Recent insights in BIP pathogenesis have indicated that a key feature is deregulated mechanisms of tissue repair that are driven by profibrotic cytokines. Here we describe a patient with lifethreatening BIP who was completely cured with imatinib mesylate (IM) after steroids and all other therapies had failed.

PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models

BackgroundEnhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death.MethodsWe investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role.ResultsTrabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.ConclusionsPARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.

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

BackgroundNuclear 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 presentationA 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.ConclusionsThe 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.

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.

Long-term response to first-line pazopanib therapy in mRCC patients: A multicenter Italian experience

Background/Aim: The specific characteristics of patients who are most likely to benefit from pazopanib therapy are still uncertain. We report on the results of an Italian multicenter, retrospective analysis investigating the factors associated with longer response to first-line pazopanib in patients with metastatic renal cell carcinoma. Patients and Methods: Adult patients were considered if they had received treatment with pazopanib (800 mg/day) for >12 months in the first-line setting. Results: In total, 112 patients were evaluated. Median duration of pazopanib treatment was 22.6 months (IQR 17.8 months). Median PFS was 22.6 months (95%CI= 20.2-25.0). Eighty-three patients (74.1%) had a PFS ≥18 months. Median OS was 32.9 months (95%CI=30.2-35.6). At statistical analysis, only PS score (1+ vs. 0) was significantly associated with PFS (HR=1.76; 95%CI=1.02-3.05; p=0.04). Conclusion: Pazopanib therapy may be suitable for all patients with mRCC, and especially in those with PS 0.

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

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 Basirico, 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.

350 Poly (ADP-ribose) Polymerase-1 (PARP-1) Inhibitors Potentiate Trabectedin Activity in Preclinical Models of Bone and Soft Tissue Sarcomas

Background: Trabectedin (TR) is a DNA-binding alkaloid approved in Europe for the treatment of soft tissue sarcoma as second/third line therapy. TR binds to the minor groove of DNA and interferes with gene transcription and nucleotide excision repair, inducing DNA double strand breaks (DSBs), and S/G2 cell cycle arrest. There is a strong clinical interest to increase TR activity by combination with other anti-cancer drugs. PARP-1 inhibitors (PARP1-i) which disable DNA base-excision repair mechanism causing the accumulation of DSBs, look like a worth to explore TR therapeutic partners. We focused our in vitro studies on the effects of the combination of TR with the PARP1-i olaparib (OL) and veliparib (VEL). Methods:We explored DNA damage by comet assay and phospho-histone H2AX determination and PARP-1 activity by polyADPribosylation assay in a panel of sarcoma cell lines treated with TR, OL,VEL and combinations. We evaluated cell viability after 72h treatment with escalating doses of TR (0−2nM), PARP1-i (VEL:0−80mcM; OL:0−20mcM), and their constant combinations. Following colony formation, cell cycle, apoptosis and DNA damage response were checked. Results: We demonstrated that TR-induced DNA damage and PARP1 activation in sarcoma sensitive cell line. The addition of PARP1i completely blocked basal and TR-induced PARP-1 activation. DNA damage response and checkpoints (ATM, ATR, BRCA1, CHK1, CHK2, p53) are activated after treatments with single agents and combinations inducing cell cycle arrest in S/G2 phase. This block was release after 48h in single agents-treated cells but not in combinations-treated cells leading to apoptotic cell death. Colony growth assay and viability tests revealed a strong synergism of the two drugs (Combination Index leyomiosarcoma > osteosarcoma undifferentiated pleomorphic > fibrosarcoma the most resistant). Determination of molecular markers of sensitivity and in vivo antitumoral activity studies are ongoing. Conclusions: Our results validate the biological rationale to combine TR and PARP1-i in sarcomas and suggest exploring this pharmacological approach in the clinical setting.