bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implications of HER family inhibition in targeted therapy of ovarian cancer
Authors: Bull S. L. , Schorge J. O. , Peyton M. J. , Xiang L. , Miller D. S. , Minna J. D. , Lea J. S. 
Published: March 2020

13120 Background: The human epidermal receptor (HER) family couples binding of extracellular ligands to intracellular tyrosine kinase (TK) signal transduction pathways, contributing to cellular proliferation. Overexpression of HER family members has been associated with poor prognosis in ovarian cancer. There is growing evidence to support that none of the individual HER members can be considered as the stand-alone target in ovarian cancer and that cooperation between them influences therapeutic response. To evaluate this receptor cooperation in ovarian cancer our goal was to determine HER family expression and to quantify inhibition of HER1 alone compared to inhibition of HER1/HER2 combined. Methods: HER1, HER2, HER3 and HER4 expression was determined by Western blot in 9 ovarian cancer cell lines. Ovarian cancer cell proliferation was determined after inhibition of HER1 using the monoclonal antibody cetuximab, the TK inhibitor gefitinib, or combination of the two. To quantify the combined inhibition of HER1/HER2, 3 cell lines were selected with variable HER1 and HER2 expression. Cell proliferation was then determined in these 3 cell lines after treatment with cetuximab combined with the monoclonal HER2 antibody, trastuzumab. IC50 values were calculated for all treatment arms and compared. A lung cancer cell line (HCC827), with a HER1 TK mutation and sensitivity to gefitinib and cetuximab, was used as a positive control. Results: HER1 was overexpressed in 3/9 ovarian cancer cell lines, HER2 in 1/9, HER3 in 2/9, and HER4 in 4/9. Minimal to no growth inhibition was seen in the 9 cell lines after blocking HER1 with cetuximab, gefitinib, or the combination of both. In the 3 cell lines selected for HER1 and HER2 expression, there was no growth inhibition achieved despite combining cetuximab with trastuzumab. However, this treatment combination increased resistance in 1 of the 3 cell lines (HCC60), noted to overexpress HER1, 2, and 4. Conclusions: Ovarian cancer has variable HER family expression. No correlation was found between HER1 and HER2 overexpression and response to their targeted inhibition. Our findings support the concept the entire HER family plays a role in ovarian cancer growth and suggest an equilibrium shift of HER heterodimerization may play an important role in maintaining cell signaling. No significant financial relationships to disclose.
Investigation of peptomimetics of GD2 antibodies as targeted therapy against human small cell lung cancer in-vitro
Authors: Wan J. , Saragovi H. U. , Conway H. , Ivanisevic L. 
Published: March 2020

13128 Background: GD2 is a well-established target that has been validated for neuroblastoma and small cell lung cancer. The therapeutic and diagnostic use of monoclonal antibodies directed to GD2 in small cell lung cancer is well documented. It has been shown that the binding of GD2 monoclonal antibodies alone can induce growth suppression and cell death of small cell lung cancer cells in-vitro. Our laboratory has developed synthetic small molecule peptomimetics as ligands of GD2. Peptomimetics have favorable in-vivo pharmacological properties compared to antibodies with no immunogenicity, longer half-lives, low toxicity, good tissue penetration, biodistribution and high target selectivity. This study proposed to determine the efficacy of peptomimetics of GD2 antibodies against small cell lung cancer cells in-vitro. Methods: 2 human cell lines were studied. H69 is a classic small cell lung cancer and H82 is a morphological variant small cell lung cancer both of which have been reported in the literature to express GD2. Cell surface expression of ganglioside GD2 was analyzed by flow cytometry (FACScan, BD Biosciences) using GD2 mAB 3F8 and GD2 mAB ME361. Cell proliferation was assessed using standard MTT assays with serum containing medium and cultured for approximately 3 doubling times for each cell line. The cell lines were exposed to increasing doses of GD2 specific peptomimetic to a maximum of 25 uM with controls including serum containing media with and without a GD2 negative peptomimetic and assessed for cell proliferation. Results: GD2 expression was confirmed for both cell lines- H69 and H82 using FACs. Exposure of the GD2 specific peptomimetic clearly caused growth suppression on the range of 35–40% when compared to controls. A dose response relationship was demonstrated with a plateau beyond 10 uM concentrations. Each experiment repeated ≥ 3 occasions. Conclusions: We have shown that attachment of GD2 specific peptomimetics can cause decreased cell proliferation in 2 small cell lung cancer cell lines H69 and H82. We have shown that there is a dose response relationship by which these compounds reduce cell viability. Peptomimetics of GD2 antibodies show promise as a targeted therapy for small cell lung cancer in-vitro and warrant further study. [Table: see text]
The addition of prednisone (Pr) to the combination of docetaxel (T) and perifosine (P) decreases the severity of gastrointestinal (GI) toxicity
Authors: Bernhardt B. , Nemunaitis J. J. , Ebrahimi B. , Cervera A. , Birch R. , Richards D. A. , Smith G. B. , Allerton J. P. , Henderson I. C. 
Published: March 2020

13142 Background: Miltefosine (M) is an alkophosholipid with activity as a topical treatment for cutaneous breast cancer lesions. Severe GI toxicity limited its development as a systemic anticancer treatment. P is an equipotent derivative of M with less GI toxicity, but nausea,(N), vomiting (V) & diarrhea (D) are still dose limiting. Methods: This phase 1 study evaluated whether the addition of Pr would enhance the tolerability of P & T in combination. Twenty-five patients (pts) were enrolled. The dose of T was 75 mg/m2 on day 8 of a 21 day cycle and half of the pts were randomized to also receive Pr, 5 mg bid. 50 mg of P was given orally 1, 2 or 3 times a day in successive cohorts on days 1 - 14 of each cycle. Results: Disease sites included lung 9, prostate 7, pancreas 3, ovary 2, breast 1 and other 4. The median age was 63 (range 41 - 80). 18 pts were male & median ECOG performance status was 1 (range 0–2). 22 pts had received a median of 2 prior chemotherapy regimens, 15 a prior taxane and 16 prior radiotherapy. Forty-two cycles of T+P were given without Pr (median 3 & range 1 - 18 per pt) and 84 cycles were given with Pr (median 4.5 cycles & range 1 - 17 per pt). The percentage of pts experiencing various grades (Gr) of N, V & D without and with prednisone are shown in the table below: Five of 12 pts not receiving Pr had gr 2 or 3 toxicities compared to 1 of 13 given Pr. (p<0.05) There were 7 pts evaluable for response not receiving Pr of whom 2 patients with prostate cancer had stable disease for 4+ and 10+ months. There were 9 evaluable pts receiving Pr; 3 partial responses (1 lung & 2, prostate pts) were seen and 1 prostate cancer was stable for 10 months. Patients given prednisone increased their average time on treatment by 50%, and this might be the reason that more responses were seen in this group. Conclusions: These data show that Pr decreases the severity of GI toxicity seen with T & P together and provide a rationale for further studies evaluating the effects of Pr on the toxicities of P either alone or in combination with other drugs. [Table: see text] [Table: see text]
Effect of pan-inhibitory somatostatin analogues, topotecan and bortezomib on the human enterochromaffin neoplastic cell line KRJ-I
Authors: Kidd M. , Eick G. , Pfragner R. , Murren J. , Culler M. , Modlin I. M. 
Published: March 2020

13144 Background: Effective therapeutic options to inhibit the growth and limit the spread of carcinoid tumors are limited. Somatostatin (SST) analogs that target specific SST receptors, though often effective at alleviating the symptoms of carcinoid disease, have limited cytostatic effects on carcinoid tumor cells. The anti-proliferative activity of 2 pan-inhibitory SST analogues and lanreotide were evaluated using the human small intestinal carcinoid cell line KRJ-I. The effects of novel cytotoxic agents used in Phase II carcinoid clinical trials, topotecan (topoisomerase-I inhibitor) and bortezomib (proteasomal inhibitor), were also measured. Methods: The SST receptor profile of KRJ-1 cells was determined using hybridization to U133A chips and confirmed by real time PCR with Taqman probes for SSTR1–5. KRJ-1 cells in serum-free medium were treated with 100 pM to 10 μM of the SST pan inhibitory analogs, BIM-23A719 and BIM-23A779, or lanreotide (BIM-23014C) and 1nM to 1 μM of topotecan or bortezomib for 72 hrs. The 3-(4,5-dimethylthiazole-2 yl)-2,5 diphenyltetrazolium bromide (MTT) assay was used to evaluate proliferation which was expressed relative to control cells (no agent added). Results: KRJ-I cells co-express mRNA for SSTR2 and SSTR3 (mean levels ± SEM 0.48 ± 0.13 and 0.73 ± 0.19 copy/copy GAPDH respectively). BIM-23A719 inhibited growth maximally (15 ± 2% of control) at ICmax = 10 pM, whereas BIM-23A779 inhibited growth maximally (11 ± 1% of control) at 100 pM. Lanreotide had no significant inhibitory effect on cell growth and resulted in increased MTT conversion at high concentrations (10 μM). Topotecan and bortezomib inhibited growth maximally at 23 ± 1.5%; ICmax = 50 nM and 32 ± 1.6%; ICmax = 50 nM respectively. Conclusions: Cytotoxic agents are more effective but less sensitive than pan-inhibitory somatostatin analogues for the inhibition of proliferation of the small intestinal carcinoid KRJ-I cell line. The specific SSTR2/3/5 analogue, lanreotide, had no inhibitory effect on KRJ-I proliferation. These results suggest that the KRJ-I cell line is more sensitive to analogues targeting a pan-somatostatin receptor profile than cytotoxic agents. The former may have potential as adjuvant agents for treatment of GI carcinoid tumors. [Table: see text]
Prolonged response to oral gefitinib, topotecan and cyclophosphamide in relapsed/resistant pediatric tumors
Authors: Donfrancesco A. 
Published: March 2020

13165 Background: Continuous schedule oral chemotherapy might be a suitable approach for resistant/relapsed pediatric tumors. Gefitinib (G) is an Epidermal Growth Factor Receptor (EGFR, HER1) inhibitor with documented activity in phase I/II adult tumor studies harboring activating mutations in the EGFR gene. Oral topotecan (TPT) and cyclophosphamide (CPM) in association have shown activity in a recent phase I study in pediatric patients (pts). Our study was aimed at evaluating the feasibility of a regimen based on oral G combined with oral TPT and CPM in pretreated pediatric pts. Methods: Pts received oral CPM (50 mg/m2/day) followed by TPT (0.8 mg/m2/day) plus G at the fixed dose of 250 mg/day for 14 consecutive days in an outpatient setting. Courses were repeated every 28 days and response was evaluated every two courses. EGFR mRNA expression in primary tumors was assessed by RT-PCR. Results: 7 pts (5M/2F), median age 8.7 years (range 4.4–22.5) were enrolled: 4 neuroblastoma (NB) pts relapsed after PBSCT and 3 sarcoma pts (1 rhabdomyosarcoma and 2 synovial sarcomas). 5 pts had PD at the time of inclusion, while 2 pts had SD after salvage therapy. Variable levels of EGFR mRNA were detected in 6/7 tumors, the only negative case being the rhabdomyosarcoma. A median of 6 courses (range 1–14) were administered. After a median follow-up of 7 months (range 3–15), 3 pts are DOD (1, 3, 8 months) and 4 pts are alive: 1 with PD, 2 with SD and 1 with CR at 13+, 7+, 7+ and 15+ months since inclusion, respectively. Median PFS was 7 months (range 1–15). Toxicity was mainly hematological (neutropenia), grade 4 according to CTC in 3/7 pts; cutaneous (rash) grade 2 and hepatic (LFT increase) grade 3 toxicity was reported in 1 pt each. 2 episodes of neutropenic fever (1 sepsis) were recorded. Conclusions: This regimen was feasible and well tolerated; a median PFS of 7+ months is encouraging and deserves further evaluation. Of the 4 NB pts, 2 are progression free at 7+ and 15+ months since inclusion (9 and 22 months after relapse). If the preliminary results reported in NB pts will be confirmed, this oral chemotherapy could be evaluated in the setting of minimal residual disease after megatherapy. No significant financial relationships to disclose.
A phase I study of triapine in combination with doxorubicin in refractory tumors
Authors: Chang J. E. , Morgan Meadows S. , Traynor A. , Kolesar J. , Marnocha R. , Lee F. , Eickoff J. , Beth E. , Binger K. , Wilding G. 
Published: March 2020

13168 Background: Triapine (T) is a novel ribonucleotide reductase inhibitor, affecting the M2 subunit. It has in vitro and in vivo antitumor activity. Hematologic toxicity was dose limiting in single agent phase I trials. Triapine potentiates the activity of DNA damaging agents such as doxorubicin (D), with synergy demonstrated in vivo. Methods: D was administered on day 1 and T was administered on days 1–4 of a 21-day cycle. Patients enrolled in cohorts of three, beginning at D60 mg/m2 and T25 mg/m2. Dose limiting toxicity was defined as grade 3 or 4 leukopenia or thrombocytopenia lasting 7 days, febrile neutropenia or grade 3 or 4 non-hematologic toxicity. Results: Fourteen patients have enrolled in four dose cohorts, receiving 23 courses. At dose level 2 (D60 mg/m2, T45 mg/m2), two patients experienced DLT (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients enrolled at dose level one without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (D45 mg/m2, T45 mg/m2). Two patients enrolled on this level had DLT. Enrollment was planned to resume at dose level 1 (D60 mg/m2, T25 mg/m2); however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Enrollment has begun at doses of D45 mg/m2 and T25 mg/m2. Hematologic toxicity has predominated, with 52% of courses having grade 3 or 4 neutropenia. Non-hematologic toxicity included grade 2 fatigue in 17% of courses and 1 episode of grade 5 heart failure. Although no objective antitumor responses have been seen, 1 patient with metastatic melanoma had stable disease through 6 cycles of treatment. Another patient with previously rapidly progressive metastatic melanoma had stable disease for over 2 months of treatment. Conclusions: The combination of triapine and doxorubicin appears to have increased toxicity. Enrollment continues. [Table: see text]
Downregulation of PLK1 elevates chemosensitivity of various breast cancer cell lines in vitro and in vivo
Authors: Spaenkuch B. , Heim S. , Kurunci-Csacsko E. , Lindenau C. , Kaufmann M. , Strebhardt K. 
Published: March 2020

13169 Background: A central role for polo-like kinases (PLK) in regulating mitosis has been shown in different species. Overexpression of PLK1 is observed in various human tumors, and it is a negative prognostic factor in patients suffering from diverse cancers. In order to reduce side-effects exerted by commonly used anti-neoplastic agents and to enhance chemosensitivity of different breast cancer cell lines, we used phosphorothioate antisense oligonucleotides (ASOs) targeted against PLK1 together with Paclitaxel, Carboplatin and Herceptin. Methods: We used different HER2-positive and -negative breast cancer cell lines (BT-474, MCF-7, MDA-MB-435) to define the role of reduced PLK1 expression for the necessary dose of anti-neoplastic agents. After transfection with PLK1-specific ASOs these agents were added and cell proliferation, cell cycle distribution, and apoptosis were measured. Results: We observed synergistic effects after combination of very low doses of PLK1-specific ASOs with Paclitaxel and Herceptin. Using Carboplatin we could only observe a synergistic effect in MDA-MB-435 cells. Downregulation of PLK1 levels led to an elevated percentage of cells in G2/M. Apoptosis and G2/M arrest were increased after combination of PLK1-specific ASOs with Paclitaxel in MDA-MB-435 cells. In a human Xenograft experiment using MDA-MB-435 cells the combination of PLK1-ASOs with Paclitaxel led to synergistic reduction of tumor growth after three weeks treatment compared to either agent alone. Conclusion: This study suggests that antisense inhibitors against PLK1 at well tolerated doses may be considered as cancer therapeutic agents which elevate chemosensitivity especially against Paclitaxel in very low doses with a significant better outcome than each agent alone. No significant financial relationships to disclose.
Metastatic Colorectal Cancer Treatment to progression or Not?
Authors: Melosky B. , Lohrisch C. , Kollmansberger C. , Gill S. , Kennecke H. , Shah A. , Coldman A. , Phillips N. , Lim H. 
Published: March 2020

13511 Background: Treatment until progression or planned interruption of first line chemotherapy is common in the therapy for metastatic colorectal cancer and are upon the discretion of the oncologist. A retrospective analysis was performed to determine the impact of these differing therapeutic strategies on overall survival. Methods: Eligible patients were treated between 2002 to 2004 in British Columbia. All patients received chemotherapy with both FOLFOX and FOLFIRI, either first or second line. Records were retrospectively reviewed for treatment interruption, efficacy and toxicity. Overall survival was the primary endpoint. Results: 101 patients were identified. Twenty-three patients who progressed before receiving 8 cycles of chemotherapy and 9 patients who stopped their chemotherapy due to toxicity were excluded. The remaining patients were analyzed for survival. Twenty-three patients were treated to progression of whom 6 received first line FOLFIRI and 17 received first line FOLFOX. The mean number of cycles of first line therapy was was 11.5. Forty six patients received a planned break. Of these, 21pateints received first line FOLFIRI and 25 patients received first line FOLFOX. Mean number of cycles of first line therapy was 9.7. Median survival of patients treated to progression was 16 months compared to 22 months for patients with planned break of therapy (p=0.003). The Hazard ratio was 2.3 (p=0.01) in favor of patients who had a planned break. Uni-variate and multivariate analysis showed no significance of sex, age, site (colon versus rectal), sequence and ECOG status as predictive factors. Conclusion: In this study, patients who were treated until progression with first line chemotherapy with either FOLFOX or FOLFIRI had an inferior survival. Possible explanations for the detrimental hazard ratio for patients treated to progression are decreasing reserve for second line therapy when first line therapy is prolonged and increasing resistance to 5-FU based therapy with prolonged exposure. As this is a retrospective, observational study, other variables not captured by the modeled covariates that may have influenced results. This data suggests that treating to best response and then allowing a break does not detrimentally affect survival. No significant financial relationships to disclose.
Preoperative radiation in combination with uracil/tegafur (UFT) and mitomycin C (MMC) in locally advanced rectal adenocarinoma
Authors: Gemici C. , Mayadagli A. , Salepci T. , Yaprak G. , Seseogullari O. O. , Tugrul F. 
Published: March 2020

13512 Background: Preoperative chemoradiation has become the standard treatment approach not only for tumor downstaging, but also for adjuvant treatment of locally advanced rectal adenocarcinomas (Sauer et al. NEJM 2004). The most commonly used chemotherapeutic agent with preoperative radiation is either bolus or infusional 5-fluorouracil (5-FU). These combinations produce pathologic complete responses in the range of 10–30%. Continuous infusion of 5-FU has proven to be superior to bolus 5-FU, when given during radiation. However widespread use of continuous infusion 5-FU has been limited by the need for an indwelling venous catheter and portable infusion pump. UFT acting like infusional 5-FU, offers the advantage of oral administration. Response to preoperative chemoradiation is associated with higher sphincter preservation and survival rates. UFT, MMC (a hypoxic cell cytotoxin) combination during preoperative radiation may improve the response rates. The aim of this study is to assess the efficacy (pCR) and toxicity of this combination. Methods: 26 patients with biopsy proven non metastatic rectal adenocarcinoma were included. Clinical T and N stages, determined by pelvic MRI were; 10/26 cT3, 16/26 cT4, 10/26 cN0, and 16/26 cN+. Pelvic radiotherapy was administered with 6 or 15 MV photons to 46 Gy in 23 fractions over 5 weeks, with four field technique in prone position. During radiotherapy, patients received UFT, 300 mg/m2 divided in two daily doses, five days a week, from Monday to Friday, starting on the first day, ending on the last day of radiation, together with bolus injection of MMC, 10 mg/m2, once in the morning of the first day of radiaton. Surgery was performed 6 or more weeks after the radiation treatment has ended. Results: Acute grade III/IV toxicity was observed in 6 out of 26 patients. Diarrhea, 3 grIII, 1 grIV. Neutropenia, 1 grIII. Dermatitis, 1 grIII. Tumor downstaging was observed in 16 patients out of 26 (62%). Nodal sterilization was obtained in 11 patients out of 16 (69%), with a pathologic complete response in 3 out of 26 patients (11%). Conclusions: Preoperative radiation concurrent with UFT and MMC has a good activity, with manageable acute toxicity. No significant financial relationships to disclose.