bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using hapmap tools to predict oncology-related phenotypes: TPMT activity vs hapmap SNPs
Authors: Jones T. , Yang W. , Evans W. , Relling M. 
Published: March 2020

13035 Background: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme responsible for the S-methylation of thiopurines. There are several functional genetic polymorphisms in TPMT activity, which can lead to drug toxicities; however, among individuals with high TPMT activity, a substantial portion of enzymatic variability remains unexplained. B-lymphoblastoid CEPH cell lines have been genotyped at over 2 million single nucleotide polymorphisms (SNPs) as part of the International HapMap project. Therefore, extensive phenotype-genotype association studies can be conducted in these cell lines by systematic determination of cancer-related phenotypes. Methods: We measured the phenotype of TPMT activity in 82 CEPH cell lines. Of these, 53 had expression data available on over 8000 genes from Affymetrix Focus Array technology. We evaluated whether TPMT activity was associated with HapMap SNPs in TPMT (cis SNPs), genome-wide HapMap SNPs (trans SNPs), and level of gene expression using Kruskal-Wallis test and Spearmans rank correlation. Results: We found associations of TPMT activity with four SNPs (p < 0.05) in TPMT (± 100K bp), one of which (rs1142345, p = 0.009) is a known functional SNP responsible for TPMT deficiency. Two other significant SNPs are in linkage disequilibrium with rs1142345. Associations were also found with 1598 trans SNPs across the genome (p < 0.001). TPMT activity was associated with the expression of eight genes (p < 0.0001, FDR <20%). The only overlapping trans gene is PACSIN2, whose expression most significantly correlated with TPMT activity and also contains two significantly predictive trans SNPs. Conclusions: The CEPH cell lines were useful in that a known functional variant, rs1142345, (serving as a positive control) was associated with TPMT activity, and that additional polymorphisms in TPMT and in potentially important trans-acting factors have been identified as possible additional genomic determinants of TPMT activity. Similar experiments with other phenotypes can likewise capitalize on this publicly available resource. With further validation, these studies may lead to discovery of additional candidate polymorphisms that can lead to further optimization of thiopurine therapy in the clinic. No significant financial relationships to disclose.
A phase II trial of docetaxel, thalidomide, bevacizumab, and prednisone in patients (pts) with metastatic androgen-independent prostate cancer (AIPC)
Authors: Ning Y. M. , Arlen P. M. , Gulley J. , Latham L. , Retter A. , Wright J. , Parnes H. , Pinto P. , Figg W. D. , Dahut W. L. 
Published: March 2020

13037 Background: Angiogenesis plays a vital role in progression of prostate cancer. Antiangiogenic agents’ thalidomide (Td) and bevacizumab (Bv) have been shown in Phase II trials to enhance docetaxel (Doc) activity in metastatic AIPC. Td plus Doc also improved median overall survival as compared to Doc alone. Td and Bv have different antiangiogenic mechanisms. Td appears to affect bFGF, alter circulating endothelial cells and inhibit TNF expression; yet Td does not affect the target of Bv (VEGF). Since tumor angiogenesis is a complex interplay of multiple angiogenic factors, we reasoned that combination of mechanistically different antiangiogenic agents Td and Bv with Doc might be associated with an adequately high and durable PSA response to merit further study. Methods: Pts have progressive, metastatic AIPC, with no prior chemotherapy for AIPC, or prior Td or Bv. Treatment consists of Doc 75 mg/m2 plus Bv 15 mg/kg day 1, q 21 days as a cycle (C), plus Td 200 mg qhs and prednisone10 mg qd. Enoxaparin 1 mg/kg/d sq is used for thrombosis prevention. PSA is assayed q C and radiographic studies are performed at C 0, C 2, & then q 3 Cs. Results: To date, 22 of planned 60 pts have been enrolled, median age 65 [54–79], Gleason score 8 [Gs 6∼7: 32%, Gs 8∼10: 68%], on-study PSA 111 ng/ml [7.7–4399], & pre-treatment PSA doubling time 1.7 months [0.8–18.2]. I) All 22 pts are actively on trial without progression, with median treatment 6 Cs [1–12]. II) 20 pts treated ≥ 2 Cs, 17 (85%) had PSA declines of >50%, 2 declines of >20%, and 1 stable; median duration of >50% PSA decline is 5 Cs [0∼11]. III) 14 pts (of the 20) treated ≥ 5 Cs, 13 (93%) had >50% PSA declines; 6 of them also had measurable disease: 1 CR, 2 PR, & 3 SD (50% RR). IV) Significant toxicities include grade 4 neutropenia (11/22), grade 3 febrile neutropenia (3/22), syncope (2/22), & colon perforation (1/22). No thrombosis was seen. Conclusions: This trial tests a novel strategy of improving conventional treatment of metastatic AIPC. Our data show that the combination of two mechanistically different antiangiogenic agents Td and Bv with Doc does result in a high durable response in PSA (85∼93%) with acceptable toxicities, suggesting that further studies with the combination are warranted. Accrual is continuing. No significant financial relationships to disclose.
A phase I clinical study of safingol followed by cisplatin: promising activity in refractory adrenocortical cancer with novel pharmacology
Authors: Carvajal R. D. , Merrill A. H. , Dials H. , Barbi A. , Schwartz G. K. 
Published: March 2020

13044 Background: Safingol (L-threo-dihydrosphingosine), originally identified as a competitive inhibitor of protein kinase C, has been re-identified as an inhibitor of sphingosine kinase (SK). Inhibition of SK induces apotosis and autophagy by increasing intracellular conversion of sphingosine to ceramide. In vivo, safingol enhances the antitumor activity of cisplatin in a sequence dependent manner (safingol→cisplatin). Methods: We designed a phase I trial of escalating doses of safingol (60→120→240→ 360→480→600 mg/m2) followed 1 hr later by fixed-dose cisplatin 75 mg/m2 given q21 days in pts with advanced solid tumors. Standard phase I eligibility critieria apply. Prior cisplatin is allowed. Results: 13 evaluable pts have been enrolled: 5 male/8 female, median age 54 (range 36–68), median KPS 90% (range 80–100%), mean number of priors 2.8 (range 1–6). 2 dose limiting toxicities (DLT) were observed with escalation of safingol to 240 mg/m2 (gr 3 fatigue, gr 3 hyponatremia), both felt to be due primarily to cisplatin. The protocol was amended to reduce cisplatin to 60 mg/m2, given with 240 mg/m2 of safingol. We observed 1 DLT (persistent gr 3 thrombocytopenia) at this dose level. Pharmacokinetic (PK) analysis by mass spectroscopy shows nearly complete clearance of safingol from circulation within 24 hours of treatment with a 10-fold greater amount of safingol in whole blood than in plasma. An increase in sphingosine and dihydroceramide levels were observed with therapy, and N-acyl- and N-methyl- metabolites of safingol were detected. We observed 1 PR (4+ months) in a pt with cisplatin-refractory adrenocortical cancer metastatic to the liver and lung after only 1 cycle of therapy. 1 additional pt with adrenocortical cancer has SD (2+ months) on therapy. Conclusions: Escalating doses of safingol can be safely administered with a fixed dose of cisplatin. PK data reveal acyl- and methyl-safingol for the first time in human plasma, with a significant fraction of safingol bound to human blood cells. We observed unusual activity in pts with adrenocortical cancer. Further dose escalation of safingol with cisplatin 60 mg/m2 is ongoing, and additional PK data and complete sphingolipid profiles will be presented. (Supported by NCI R21-CA112910). No significant financial relationships to disclose.
NGRhTNF, a new vascular targeting agent with a dual mechanism of action: preliminary clinical results
Authors: Bordignon C. , Caligaris Capio F. , Toma S. , Manenti L. , Rizzardi P. , Curnis F. , Gallo Stampino C. , Corti A. 
Published: March 2020

13052 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding solid tumor (lung, renal, and colorectal) neovasculature. NGRhTNF specific binding relies on dynamic interactions with TNF-receptors, aminopeptidase N (CD13) and a specific integrin: a combination of receptors expressed by the tumor neovasculature endothelium, but not on normal vessels. This combination provides NGRhTNF with unique biological properties: at low dose, increased tumor vascular permeability, and massive tumor necrosis at high dose. Mouse preclinical data confirmed these properties, revealing also strong synergy between low dose NGRhTNF and cytotoxic agents (antracyclines, platinum based compounds, etc.). Methods: Based on these data, a series of studies were designed. A multicentre phase I study with NGRhTNF as single agent -still in progress- aims at defining MTD and preliminary anticancer activity, within the EORTC network (EORTC 16041). A single center phase I study exploiting the low dose range (0.2–1.6 μg/m2) aims at defining safety and NGRhTNF activity on the tumor vascular permeability using DCE MRI (HSR NGR002). Results: Twelve advanced neoplastic patients were enrolled in the HSR NGR002 study. Up to the dose of 1.6 μg/m2, the only common toxicity was represented by constitutional symptoms such as infusion-associated chills (40%) of mild to moderate intensity. At the tested doses, NGRhTNF increased vascular permeability, as shown by changes in DCE MRI parameters (Ktrans and Kep), and modulated the expression of chemokines possessing antiangiogenic activity. NGRhTNF achieved stable disease in about 45% of highly refractory treated patients, and still ongoing long lasting disease control in 2 cases (7 and 9 months along with sharp decline of CA125 and VEGF). Conclusions: NGR-hTNF, a VTA with a unique mechanism of action, combines activity on tumor vascular permeability and direct anti-cancer effect. Preliminary data in humans confirm its favourable safety profile along with remarkable anticancer activity, thus rendering the agent suitable for a development program alone or in combination with chemotherapeutics. Phase II low dose combination studies will begin in 2006. [Table: see text]
ERCC1 expression as a predictor for chemosensitivity in recurrent colorectal cancer patients receiving cisplatinum (CDDP) plus S-1 chemotherapy
Authors: Uchida K. , Hayashi K. , Kuramochi H. , Kudo K. , Miyakura S. , Fujita I. , Yamamoto M. , Danenberg K. D. , Danenberg P. V. , Takasaki K. 
Published: March 2020

13065 Background: To test the hypotheses of whether the relative mRNA expression of excision cross complement-1 (ERCCI) are associated with response to CDDP+S-1 chemotherapy in recurrent colorectal cancer (CRC). We assessed the relationship between ERCC1 mRNA expression levels and the response. Methods: Thirty four patients with relapsed CRC were treated with cisplatin 30 mg/m2 on Day 1 and Day 8, and S-1 twice daily (BSA = 1.5 m2, 60 mg/day) for 21 days, followed by a 2-week period of no treatment. cDNA was derived from paraffin-embeded tumor specimens to determine ERCC1 mRNA expression relative to the internal reference gene beta-actin using fluorescence-based, real-time reverse transcriptase polymerase chain reaction (Taqman) system. Results: Among 34 CRC patients, 4 patients were evaluated as CR, 13 as PR, and 17 as NC/PD. Relative ERCC1 mRNA gene expression level showed significant difference by the response with median expression levels of 0.70/1.33/1.80 in CR/PR/NC+PD patients respectively (P = 0.04). Conclusions: These data suggest that intratumoral ERCC1 mRNA expression levels are independent predictive markers of response to CDDP+S-1 chemotherapy in colorectal cancer. No significant financial relationships to disclose.
Mechanisms of resistance to low-dose metronomic cyclophosphamide
Authors: Emmenegger U. , Chen L. , Shaked Y. , Francia G. , Kouri A. , Mutsaers A. J. , Ebos J. M. , Man S. , Kerbel R. S. 
Published: March 2020

13079 Background: It has been postulated that antiangiogenic therapies are less susceptible to acquired resistance compared to conventional treatment strategies, which target genetically unstable tumor cells. However, resistance is commonly seen (pre)clinically. A better understanding of the underlying mechanisms is clearly needed to improve such therapies. Methods: We studied mechanisms of acquired resistance to low-dose metronomic (LDM) cyclophosphamide (CTX), the continuous or frequent administration of comparatively low doses of CTX with no extended breaks resulting primarily in antiangiogenic effects, by using LDM CTX relapsed/resistant variants obtained during prolonged in vivo therapy from the human prostate cancer cell line PC-3, which initially is highly responsive. The variants were analyzed for their growth characteristics, angiogenic “phenotype” and impact on circulating endothelial cells (CEC)/endothelial cell progenitors (CEP). Furthermore, we obtained microvessel density (MVD) counts of corresponding xenografts and analyzed in vitro resistance to 4-hydroxycyclophosphamide (4-OH-CTX), hypoxia, acidosis, and glucose as well as serum deprivation. Results: The resistant variants did not show consistent changes in their angiogenic “phenotype”. The decrease in MVD upon LDM CTX treatment was comparable to that obtained in xenografts from parental PC-3, which was reflected by similar changes in the number of CEC and CEP. Despite in vivo resistance to LDM CTX, there was no evidence of in vitro resistance of the variants to 4-OH-CTX. However, they exhibited increased tolerance to microenvironmental stress resulting from sustained antiangiogenic activity. Conclusions: In this model, resistance to LDM CTX develops despite sustained antiangiogenic activity. This provides further evidence that reduced vascular dependence of the tumor cell population may be a basis for the observed resistance. The administration of CTX in a LDM manner does not result in tumor cell CTX resistance, supporting the notion that LDM protocols target primarily the tumor vasculature. If confirmed in ongoing clinical metronomic chemotherapy trials, our results will have major implications for the management of patients that progress under such treatment. No significant financial relationships to disclose.
A phase 1 study of daily oral perifosine (P) and weekly gemcitabine (G)
Authors: Weiss S. , Nemunaitis J. J. , Diaz-Lacayo M. , Birch R. , Ebrahimi B. , Berdeaux D. H. , Allerton J. P. , Gardner L. R. , Henderson I. C. 
Published: March 2020

13084 Background: Miltefosine (M) has been shown to be synergistic with gemcitabine (G) in vitro (Georgieva Cancer Letters 182: 163–174, 2002). Perifosine (P) is a derivative of M with less GI toxicity. Methods: Twenty-two patients (pts) were enrolled on a phase 1 study to determine if G could be given at a dose of 1000 mg/m2 on days 1 and 8 of a 21-day cycle with 50 mg of P given orally 1, 2 or 3 times a day on days 1–14. Three pts were entered at each dose and the cohort expanded to 6 if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Ten additional pts were entered at the highest dose achieved. Results: Disease sites: lung 6, pancreas 3, breast 3, renal 2, sarcoma 2, other 5. The median age was 61 (range 29–82); 11 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 3, range 1–4) & 6 had received prior G. 10 pts had received prior radiotherapy. The grade 3/4 non hematologic toxicities for each cohort are given in the table below: One pt on cohort 3 died from pneumonia and sepsis unrelated to therapy after cycle 1. A median of 4 cycles (range 1 - 18) were delivered. At each dose 50% of pts had no G dose reductions. P doses were reduced in 7% of cycles (50 mg - 5%, 100 mg - 15%, 150 mg - 7%). Fifteen pts were evaluable & 4 partial responses (lung, breast, pancreas and unknown primary) were seen; 6 pts had stable disease (renal (2), sarcoma (2), liver and head/neck) for a median of 6 (range 3 - 9) months. No responder had received prior G. Pharmacokinetic (PK) studies showed that the steady state level at 150 mg was 9.47 ± 4.56 μM compared to 10.14 ± 2.02 μM in an earlier study (Crul, Eur. J. Cancer 38: 1615–21, 2002) when this dose of perifosine was used alone. Conclusions: It is concluded that full dose G can be safely administered with perifosine doses up to 150 mg with manageable toxicity and without affecting the PK of P. Phase II studies are warranted to further define the activity of the combination and the contribution of P. [Table: see text] [Table: see text]
Her2-targeted pegylated stealth liposomal doxorubicin (PLD) retains its specific targeting ability to Her2-expressing tumor cells after in vivo circulation and extravasation to mouse malignant ascites
Authors: Shmeeda H. , Tzemach D. , Mac L. , Najafi A. , Hjortsvang K. , Gabizon A. 
Published: March 2020

13097 Background: Receptor-directed targeting of ligand-bearing liposomes to tumor cells may enhance therapeutic efficacy by intracellular delivery of a concentrated payload of liposomal drug. The goal of this study was to assess whether Her2-targeted PLD retains its binding ability to Her2-expressing target cells through circulation in the blood and extravasation to the ascitic fluid of mice with malignant ascites. Methods: PLD was grafted with a pegylated lipophilic conjugate of an anti-Her2 scFv antibody fragment (F5) at a ratio of 15 ligands per liposome. BALB/c mice were injected with J6456 lymphoma cells into the peritoneal cavity to generate malignant ascites. When abdominal swelling developed, Her2-targeted PLD and nontargeted PLD were injected into the mice i.v. at a dose of 15 mg/kg. The ascitic fluid was collected 48 hr later, ascitic tumor cells were removed, and the doxorubicin levels in the cell-free ascitic fluid and plasma were determined. Binding of the liposome-containing ascitic fluid was tested in vitro against Her2-expressing human tumor cell lines (N87, SKBR-3) and compared to the binding of shelf formulations (not passaged in vivo) of Her2-PLD and PLD, using as parameter the amount of cell-associated doxorubicin. Results: Plasma and ascitic fluid levels of Her2-PLD were only slightly below those of PLD indicating that the Her2 ligand did not cause any significant change in the clearance rate of PLD. Her2-PLD and PLD bound to an equal extent to J6456 cells in vivo. The in vitro binding of Her2-PLD from ascites to Her2- expressing cells was increased 10 to 20-fold above that of PLD from ascites, similarly to the 20-fold difference in binding between shelf Her2-PLD and PLD. Conclusions: Her2-targeted PLD demonstrates similar circulation time to that of nontargeted PLD. After in vivo passage, the targeted liposome retains most of its original binding capacity to Her2 expressing cells indicating that the ligand is stably maintained in association with the doxorubicin liposomal carrier. Targeting of PLD using this Her2 antibody fragment should provide an important means of selective drug delivery to tumors expressing the Her2 receptor. [Table: see text]
Phase I study of RX-0201 in patients with advanced or metastatic solid tumors
Authors: Malik S. M. , Hwang J. , Marshall J. , Ramzi P. , Posey J. A. , Ahn C. , Lee Y. 
Published: March 2020

13102 Background: RX-0201 is a 20-mer oligonucleotide that is complementary to Akt-1 mRNA. Strong evidence exists that Akt plays a very important role in cancer progression by stimulating cell proliferation and inhibiting apoptosis. Over-expression of constitutively activated Akt in many cell types promotes cellular transformation. In addition to reducing Akt mRNA levels and inhibiting the expression of Akt protein, in vitro pharmacology studies have demonstrated that RX-0201 suppressed cell proliferation in carcinomas of the brain, breast, cervix, colon, head & neck, kidney, liver, lung, ovary, pancreas, prostate, stomach and melanoma. In vivo studies have also shown that RX-0201 significantly inhibits the growth of tumor in human prostate and brain cancer of nude mice models. This study is designed to determine the maximum tolerated RX-0201 dose in patients with advanced malignancies. Methods: Patients with solid tumors for whom no standard therapies exist, Karnofsky PS>70, adequate hepatic and renal function and normal coagulation parameters were eligible. Eligible patients were scheduled to receive 2 treatment cycles with RX-0201 via continuous infusion for 14 days with 7 days off q 21 days. Dose escalation was based on observed treatment-related toxicities. One patient was enrolled at each dose level (6 mg/m2/day - 315mg/m2/day). Tumor measurements were performed at screening and at the completion of treatment cycle 2. Tumor biopsies were obtained at screening and at the completion of treatment cycle 2 to look for inhibition of AKT in tumor cells. Plasma samples for pharmacokinetic analyses were collected. Results: To date 9 patients have been enrolled, 4 with GI malignancies, 1 with small cell lung cancer, 2 with breast cancer and 1 with locally advanced Basal Cell carcinoma. 6/9 patients were able to complete the 2 cycles.1/9 patients were taken off study because of withdrawal of consent due to grade 1 vomiting. 8 patients were taken off for disease progression. Drug related toxicities were Grade 1 and included fatigue, dizziness, cough vomiting and myalgia. Conclusions: While enrolment is still ongoing, the RX-0201 has been well tolerated upto 315mg/m2 in this previously heavily treated patient population. Once MTD is reached phase II trials will be planned. PK and PD data will be presented. [Table: see text]
Effect of simultaneous or sequential treatment with Imatinib mesylate on the radiosensitivity of U343MG glioblastoma cells in vitro
Authors: Herskind C. , Körschgen T. , Lohr F. , Hochhaus A. , Vajkoczy P. , Wenz F. 
Published: March 2020

13125 Background: In a current clinical study, the tyrosine kinase (TK) inhibitor, imatinib mesylate, is given alternately with radiotherapy in inoperable glioblastoma patients. Imatinib inhibits phosphorylation of certain protein TKs including activated Bcr-Abl, c-kit, and the PDGF receptor. To study the interaction between imatinib and irradiation, a translational study on glioblastoma cells in vitro was conducted in parallel with the clinical study. The purpose of the present work was to study the effect of simultaneous or sequential treatment of the two agents. Methods: U343MG glioblastoma cells were grown in medium supplemented with 10% foetal bovine serum (FBS) or 5% platelet poor plasma (PPP). The colony formation assay was used to test the cytostatic effect of imatinib alone and clonogenic cell survival after irradiation. The surviving fraction as function of dose was fitted by the linear-quadratic model. Results: Irradiation in dilute culture conditions showed a moderate enhancement of radiation-induced cell inactivation by 3–10 μM imatinib. The sensitising effect was similar when the medium was supplemented with PPP instead of FBS. The inhibitory effect on colony formation was the same whether imatinib was added before or after irradiation. However, the inhibitor was required to be present during colony formation since no significant effect was observed when the inhibitor was present only during irradiation and repair. Pretreatment of mass cultures with imatinib for 2–5 days had no effect on the radiosensitivity in delayed plating experiments where imatinib was absent during colony formation. Conclusions: Imatinib showed a synergistic effect in combination with radiation but did not act as a classical radiosensitiser. We suggest that the interaction of imatinib with radiation may be associated with an inhibitory effect on cell proliferation. [Table: see text]