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Background: This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro / vivo . Methods: A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1). Results: Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild–moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (⩾10 cycles in three cases). PD 0332991 was slowly absorbed (mean T max 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure. Conclusion: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.

Background: Radiation-associated breast angiosarcoma (RT-AS) is an uncommon malignancy with an incidence of less than 1 % of all soft tissue sarcomas. The overall prognosis is quite dismal with high rates of recurrences and poor overall survival. There is an obvious paucity of data regarding clinical outcomes of patients with breast RT-AS. Methods: We identified all patients with RT-AS treated at the Memorial Sloan-Kettering Cancer Center between 1982–2011 and collected their correlative clinical information. Results: We identified 79 women with RT-AS with a median age of 68 (range 36–87). The median interval between radiation and development of RT-AS was 7 years (range 3–19). The median time to local and distant recurrence was 1.29 years (95 % CI 0.72–NA) and 2.48 years (95 % CI 1.29–NA), respectively. The median disease-specific survival was 2.97 years (95 % CI 2.21–NA). Independent predictors of worse disease-specific survival included age ⩾68 years (HR 3.11, 95 % CI 1.20–8.08, P =0.020) and deep tumors (HR 3.23, 95 % CI 1.02–10.21, P =0.046.) Conclusion: RT-AS has high local/distant recurrence rates, limited duration on standard chemotherapy and poor disease-specific survival.

MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53−/− cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wild-type E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73 α and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease.

Peptide nucleic acid (PNA) oligomers are DNA mimics, which are capable of binding gene sequences 1000-fold more avidly than complementary native DNA by strand invasion and effectively obstruct transcription. Irreversibly obstructing the transcription or replication of a gene sequence, such as BRAF , offers a potential route to specifically target the cancer cell itself. We have employed PNA oligomers to target BRAF in a sequence-specific complementary manner. These PNAs have been modified by appending configurationally stabilizing cationic peptides in order to improve their cellular delivery and target avidity. Our results indicate that exposure of the melanoma cell lines to a modified PNA-peptide conjugate complementary to BRAF mutation sequence results in a concentration-dependent and time-dependent inhibition of cell growth that is specific for the BRAF -mutant melanoma cell lines with inhibition of mRNA and protein expression. Xenograft mouse trials show increased tumor growth delay and necrosis with the BRAF -complementary PNA-peptide conjugates as compared with the saline and scrambled PNA sequence controls. Similarly, quantitative measurement shows a 2.5-fold decrease in Ki67 and a 3-fold increase in terminal deoxynucleotidyl transferase dUTP nick end labeling expression with this approach. PNA-delivery peptide conjugates represent a novel way to target BRAF and represent a new approach in targeting selective oncogenes that induce tumor growth.

Chondrosarcomas are alleged to be resistant to chemotherapy. A retrospective review of our experience primarily with dedifferentiated chondrosarcomas treated with chemotherapy was performed to re‐evaluate the efficacy of chemotherapy for this tumor. There were 18 patients: 14 stage IIB and four stage III. Seventeen patients had dedifferentiated chondrosarcoma. The median age at diagnosis was 57 years. Fourteen of the patients underwent wide excision of the tumor, two underwent amputation, and two had no surgery. The femur and the pelvis were the most common locations of the primary tumor. Chemotherapy for 11 of the patients consisted of cisplatin and doxorubicin. Survival was analyzed with the Kaplan‐Meier method; the median survival was 12 months. The hypothesis that chondrosarcomas express P‐glycoprotein was tested. Expression of P‐glycoprotein was evaluated by immunostaining with use of the C494 and C219 antibodies on 41 benign and malignant cartilage tumors, six of which were from the patients in the chemotherapy group. Immunostaining revealed that 37 of 41 cartilage tumors expressed P‐glycoprotein. The rate of survival of patients with high‐grade chondrosarcoma treated with chemotherapy is poor. P‐glycoprotein expression is common in benign and malignant cartilage lesions. The lack of response to chemotherapy may be related to the expression of P‐glycoprotein.

Cyclooxygenase-2 (COX-2) is involved in antiapoptosis signaling, and its induction may require activation of protein kinase C (PKC). Safingol (SAF), a PKC inhibitor, has been shown to enhance apoptosis induced by mitomycin-C (MMC) in human gastric cancer MKN-74 cells. The aim of this study was to identify the role of COX-2 in MMC-induced apoptosis in MKN-74 cells. Protein expression of COX-2 and Bcl-2 and activation of PKCalpha were examined by Western blot analysis. Apoptosis induction was examined by staining with bisbenzimide trihydrochloride (Hoechst-33258) of condensed chromatin, which characterizes the cells undergoing apoptosis. COX-2 mRNA levels were examined by Northern blot analysis. After exposure for 1-2 h to 1 microg/ml MMC, upregulation of COX-2 and Bcl-2 protein expression was noted. The activation of PKCalpha occurred within 1 h of MMC exposure, and temporally preceded the induction of COX-2. Similar results were observed in cells exposed to the PKC activator, 3-phorbol 12-myristate 13-acetate. Cotreatment with SAF and MMC abolished the induction of COX-2 by MMC. Furthermore, NS-398, a selective COX-2 inhibitor, significantly enhanced MMC-induced apoptosis by fivefold from 4 +/- 2% (MMC alone) to 20 +/- 2% (MMC plus NS-398). There was no discernible change in COX-2 mRNA levels after a 2-h exposure to MMC but a twofold increase after a 24-h exposure. MMC upregulates COX-2 expression, which appears to be an antiapoptotic signal downstream of PKC. Selective inhibition of COX-2 can therefore provide a novel way to enhance MMC-induced apoptosis independent of inhibiting PKC.

In the paper titled “Sarcoma Immunotherapy: Past Approaches and Future Directions” in the following sentence: “Currently, there is a phase II trial of a trivalent peptide vaccine to the gangliosides GD2, GD3, and GM2 in patients with sarcoma that have had solitary metastases excised (NCT00597272),” the corrected identifier should be NCT01141491.

Quantitative reverse transcription PCR (RT-PCR) was used to measure gene expressions (relative mRNA levels) of p16 and the alternate transcript p16β in esophageal and gastric tumors. p16 gene expression was undetectable in 13 of 25 esophageal squamous cell carcinomas. In 11 of these tumors, p16β was simultaneously missing whereas two of the p16-deficient tumors still expressed p16β. Among 34 esophageal adenocarcinomas and 11 gastric adenocarcinomas, only one tumor lacked p16 expression and all tumors expressed p16β. p16 sequences were not detectable by PCR in genomic DNA from tumors lacking both p16 and p16β mRNA, suggesting that the simultaneous loss of both gene expressions resulted from homozygous genomic deletion of the p16 gene. However, DNA from tumors that lacked p16 mRNA but expressed p16β did contain the p16 gene, consistent with loss of p16 expression in these tumors by transcriptional suppression. No point mutations in p16 cDNA were detected among 12 that were sequenced, but one p16 cDNA from a squamous cell carcinoma had a 19-base deletion, possibly indicating a splice-site mutation. Among those tumors that expressed p16 mRNA, the gene expression values of both p16 and p16β varied over a wide range. In some cases, p16 expression was detectable but low, suggesting that down-regulation of p16 expression may be used in some cases to achieve the funtional equivalent of gene deletion or transcriptional silencing. These results demonstrate that p16 expression patterns differ based on tumor histology and origin. Homozygous deletion of p16 appears to be common in esophageal squamous cell carcinomas but in adenocarcinomas, both gene deletion and transcriptional silencing of p16 were infrequent.

Peptide nucleic acid (PNA) oligomers are DNA mimics, which are capable of binding gene sequences 1000-fold more avidly than complementary native DNA by strand invasion and effectively obstruct transcription. Irreversibly obstructing the transcription or replication of a gene sequence, such as BRAF.sup.V600E, offers a potential route to specifically target the cancer cell itself. We have employed PNA oligomers to target BRAF.sup.V600E in a sequence-specific complementary manner. These PNAs have been modified by appending configurationally stabilizing cationic peptides in order to improve their cellular delivery and target avidity. Our results indicate that exposure of the melanoma cell lines to a modified PNA-peptide conjugate complementary to BRAF.sup.V600E mutation sequence results in a concentration-dependent and time-dependent inhibition of cell growth that is specific for the BRAF.sup.V600E-mutant melanoma cell lines with inhibition of mRNA and protein expression. Xenograft mouse trials show increased tumor growth delay and necrosis with the BRAF.sup.V600E-complementary PNA-peptide conjugates as compared with the saline and scrambled PNA sequence controls. Similarly, quantitative measurement shows a 2.5-fold decrease in Ki67 and a 3-fold increase in terminal deoxynucleotidyl transferase dUTP nick end labeling expression with this approach. PNA-delivery peptide conjugates represent a novel way to target BRAF.sup.V600E and represent a new approach in targeting selective oncogenes that induce tumor growth.