bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sorafenib monotherapy in patients with treatment-naïve metastatic renal cell cancer: preliminary results of a phase II intra-patient dose-escalation study
Authors: Srinivas S. , Harshman L. , Hauke R. J. 
Published: August 2020

e14564 Background: In a phase I dose finding study, the maximum tolerated dose of sorafenib was determined to be 400 mg bid. In subsequent practice, these doses of sorafenib have been associated with minimal or reversible toxicity, which presented an opportunity to explore more intensive dosing. A single institution trial of 44 patients demonstrated complete responses in 26% and partial responses in 36%. 93% of patients were able to be dose escalated. The objective of our study was to confirm these findings. The primary endpoints for this study were safety, feasibility, and toxicity. Secondary endpoints included overall response rate (ORR) and progression- free survival (PFS). Methods: Patients with treatment-naïve metastatic renal cell with clear cell histology were enrolled at Stanford University and the University of Nebraska Medical Center. Cycles consisted of 28 days. Dose limiting toxicity (DLT) was defined as grade 3/ 4 toxicity. Patients received sorafenib 400mg bid for 28 days. If no DLT's were reported after the first cycle, patients were dose escalated to sorafenib 600 mg bid for cycle 2. Patients without DLTs at the end of the second cycle were dose escalated to the highest dose, sorafenib 800 mg bid. Patients continued on therapy until progression or unacceptable toxicity. Results: To date, thirteen patients have been treated. Median age was 63 (47–84) years. The majority (84%) were men. Ten patients had nephrectomy prior to trial initiation. Sites of metastases included lung, nodes, liver, adrenal glands, and bone. Dose escalation was possible in 70% of the patients. Median number of cycles was 7 (3–12). Hand-foot syndrome (skin toxicity) limited escalation in the other 30% of patients. One pathologic complete response was obtained after a patient underwent metastectomy of adrenal gland after 4 cycles. One patient achieved a partial response and seven experienced disease stabilization. Conclusions: This dose-escalation trial is ongoing. Dose escalation has been feasible in 70% of patients. The main toxicity limiting escalation was hand-foot syndrome. Thus far, dose escalation did not result in an increased number of responses as compared to the standard 800mg/d dosing. PFS data will be presented as data matures. [Table: see text]
XPA and XRCC3 gene polymorphisms and survival in esophageal cancer patients receiving neoadjuvant radiochemotherapy with cisplatin (CDDP), docetaxel (DTX), and 5-fluorouracil (FU)
Authors: Gusella M. , De Manzoni G. , Marinelli R. , Bruscagin S. , Bononi A. , Stievano L. , Ferrazzi E. , Zanoni A. , Cordiano C. , Pasini F. 
Published: August 2020

e14571 Background: The aim of the study was to evaluate if genetic polymorphism of DNA repair genes may predict pathological response and survival in patients affected by locally advanced esophageal cancer, treated with a neoadjuvant schedule including weekly DTX (35 mg/mq) and CDDP (25mg/mq), protracted venous infusion of FU (150 mg/mq/die) and concomitant radiotherapy for 8 weeks followed by surgery. Methods: Fifty-seven patients were enrolled, aged 60±7 years old. Median follow-up was 27 months. Genomic DNA was extracted from peripheral blood lymphocytes and XPA, XPD, XRCC1, ERCC1 and XRCC3 were genotyped through RFLP analysis. Associations between gene polymorphisms and pathological response and survival were analysed through Chi square test and Log rank test respectively. Results: Thirty-two patients presented complete remission (pCR) and 10 patients microfocal residual disease (pMRD); the remaining 15 patients were considered stable or non-responders (pS-NR). The event free(EFS) and overall (OS) median survival times have not yet reached; significantly better 3-year survival rates were observed after pCR than in case of pMRD and pS-NR (EFS: 87% vs 42.8%, p=0.0004; OS: 86% vs 56%, p=0.02, respectively). No association was found between pathological response or survival with XRCC1, ERCC1 and XPD polymorphisms. On the contrary, the XPA 23AA genotype showed an increased risk of recurrence (HR=3.5; 95% CI 1.3 to 43.7, p=0.02) and death (HR=4.4, 95% CI 1.9 to 78.2, p=0.009); there was a trend for reduced risk of negative pathological response with decreasing number of allele 23A : MRD and S-NR were found in 71%, 45% and 35% cases for AA, AG and GG genotypes, respectively. The XRCC3 241MetMet variant was significantly associated with increased risk of death (HR= 6.0, 95% CI 3.0 to 40.0, p=0.008); a trend toward a higher recurrence (p=0.07) and worse response (60% vs 43%) was found. Conclusions: XPA and XRCC3 gene defective variants were significantly associated with worse outcome and could predict OS in esophageal cancer patients treated with a neo-adjuvant intensive radio-chemotherapy protocol. Founded by CARIPARO, Italy No significant financial relationships to disclose.
HSP90 inhibition in HER2-positive breast cancer cells
Authors: Qadir Z. , Crown J. , Jensen M. R. , Clynes M. , Slamon D. , O'Donovan N. 
Published: August 2020

e14573 Background: HSP90 is required for the stability and activity of HER2 and downstream proteins, such as Akt, which play a key role in survival. We aimed to assess the anti-tumor effect of the HSP90 inhibitor NVP-AUY922 in HER-2 positive breast cancer cell lines. Methods: HER2 positive breast cancer cell lines with varied sensitivity to trastuzumab (Sensitive: BT474, SKBR3; acquired resistance: BT474Res, SKBR3Res; innate resistance: HCC1419, HCC1954, MDA-MB-453) were treated with the HSP90 inhibitor NVP-AUY922 (Novartis) and trastuzumab. IC50s were determined using the acid phosphatase assay. HER2, Akt and HSP90 levels were determined by immunoblotting after treatment with NVP-AUY922. Combinations of NVP-AUY922 with docetaxel, cisplatin and 5'-deoxy-5-fluorouridine (5-DFUR) were tested in BT474 and SKBR3 cells. Results: All of the HER2 positive cells were sensitive to NVP-AUY922, with IC50s ranging from 5.5 to 16.4 nM. Combined treatment with NVP-AUY922 (10 nM) and trastuzumab (10 nM) showed significantly greater inhibition of growth than either trastuzumab or NVP-AUY922 alone in BT474 and BT474Res cell lines (p<0.005). In SKBR3 and SKBR3Res cells, dual treatment with NVP-AUY922 and trastuzumab did not significantly increase response compared to NVP-AUY922 alone ( Table 1 ). Treatment with NVP-AUY922 resulted in a dose-dependent decrease in HER2 and Akt levels in trastuzumab-sensitive and -resistant cells. Combinations of docetaxel, cisplatin or 5-DFUR with NVP- AUY922 were antagonistic in both BT474 and SKBR3 cells (CI values >1). Conclusions: This study demonstrates that NVP-AUY922 has anti-tumor activity in trastuzumab-sensitive, and in both innate and acquired trastuzumab-resistant HER2 positive breast cancer cells. The antagonistic interactions observed for combinations of NVP-AUY922 with chemotherapy do not favour clinical evaluation of such combinations. However, combinations with other targeted therapies, such as trastuzumab, warrant further investigation. [Table: see text] [Table: see text]
Advanced epithelial ovarian cancer (EOC): Is there a place for maintenance therapy in patients with sub-optimal debulking?
Authors: Hariprasad R. , Kumar L. , Kumar S. , Bhatla N. , Thulkar S. , Das P. 
Published: August 2020

e14580 Background: Survival of patients with advanced epithelial ovarian cancer (EOC) with initial suboptimal debulking surgery (residual disease (>1 cm) and those with recurrent EOC is poor. We used EGFR inhibitor gefitinib for maintenance and analyzed data on safety and toxicity. Methods: Between Nov. 2004 and Dec. 2008, Patients who achieved complete response (CR) following six cycles of paclitaxel and carboplatin received gefitinib as (Group I). Similarly, patients with recurrent EOC who achieved CR following six cycles of salvage CT received gefitinib (Group II). Both groups received gefitinib 250 mg once daily till evidence of relapse. Patients were examined every month and toxicity (CTC version II) was recorded. Serum CA-125 was done once in 2 months and CAT scan of abdomen & pelvis every 6 month. The study was approved by Institute Ethics Committee and informed written consent was obtained from each patient. Results: A total of 48 patients (median age 47 years, range 23 to 63) have been recruited. Group I: 17 subjects and Group II 31 patients (1st relapse- 13, 2nd- 9, 3rd -6 & 4th relapse in 3 patients). The mean duration of gefitinib treatment is 8.77 months (Gp-I: 14.4 months, Gp-II: 5.68 months). Toxicity was mainly in the form of skin rash & diarrhea. Skin rash: 16 patients (33.3%); Group I - 8 (grade I-2, II-4, III-3,) & Group II - 8 patients (grade I-3,II-4,III-1). Diarrhea: 12 patients (25%); Group I-3, group II- 9) all grade I. Two patients had both skin rashes and diarrhea. No pulmonary or hematological toxicity was observed. Currently, 13 patients are on gefitinib (mean duration of treatment 12.6 months); in 34 patients gefitinib has been discontinued due to relapse and in 1 patient due to grade III skin rashes over face. Among 18 patients with skin toxicity, 8 continue to be disease-free compared to 6 of 30 without skin toxicity (p=0.07). Conclusions: Gefitinib was tolerated well with mild toxicities limited to skin and GIT. Correlations between EGFR expressions vs. response may help to identify patients likely to benefit from gefitinib therapy. No significant financial relationships to disclose.
TNF-a, retinoid acid and STAT4 pathways are differentially regulated by the HDAC inhibitors, SAHA, TSA and Sirtinol in Waldenstrom's Macroglobulinemia
Authors: Hunter Z. , Sun J. , Tseng H. , Hatjiharissi E. , Maghsoudi K. , Xu L. , Manning R. , Munshi N. , Anderson K. , Treon S. 
Published: August 2020

e14582 Background: HDAC inhibitors (HDAC-I) have emerged as a promising class of therapeutics for the treatment of lymphoplasmacytic malignancies, particularly in combination strategies. The basic mechanisms by which these agents modulate malignant cell growth remain to be clarified. In recent studies, we showed that SAHA, TSA, and Sirtinol have significant preclinical activity in Waldenstrom's macroglobulinemia (WM). As part of our effort to identify potential molecular targets for these agents, we performed gene expression profiling (GEP) using WM cells treated with these agents. Methods: We implemented the Bootstrap re-sampling technique on five BCWM1 GEP datasets to characterize the range of gene expression observed. Individual BCWM1 cells were treated with SAHA, TSA and Sirtinol at their established IC50 dosages for 6 and 24 hours prior to gene expression profiling. The genes which changed by two-fold, and fell outside of the 90% range of expression after drug treatment were identified. Results: SAHA upregulated TNF-α and downstream proteins including HSP70, TNFSF9, SERPINB2, as well as STAT4- dependent genes. Sirtinol upregulated metalloproteinase (MMP) and phosphodiesterase (PDE) family members through retinoic acid signaling. We also observed that SAHA, TSA and Sirtinol differentially upregulate elements of the MAP kinase pathways, including signaling through Erk, JNK, and p38 MAPK, indicating a global stress response to HDAC inhibition. Conclusions: The above studies suggest that HDAC inhibitors differentially effect growth of WM cells through both global as well as pathway specific alterations in signaling. Importantly, this data provides a platform for studying the mechanistic role of HDACs in WM, and provide a framework for the use of HDAC-I as single and combination. No significant financial relationships to disclose.
Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian patients (pts) with 5-FU and capecitabine (CAP)-related toxicity
Authors: Podoltsev N. A. , Saif M. W. 
Published: August 2020

e14588 Background: As many as 1 in 3 pts receiving 5-FU/CAP experience dose-limiting toxicity including diarrhea, hand-foot syndrome (HFS), mucositis and myelosupression. Deficiency of DPD, a rate limiting enzyme in 5-FU catabolism can lead to life- threatening complications. DPD deficiency was found to be related to > 40 sequence variations in DPYD. Known deleterious mutations explain only a limited proportion of 5-FU's adverse events. Full sequence analysis of DPYD gene increases sensitivity by 20% vs. simple identification of two most common deleterious mutations (IVS14 +1 G>A, D949V). Pretreatment detection could prevent serious, potentially lethal side effects. We present analysis of DPYD genotyping in untreated Caucasian pts (control group) and Caucasian pts with 5-FU/CAP-related grade 3/4 toxicities (toxicity group) who underwent TheraGuide 5-FU testing. Methods: Full sequencing of DPYD was performed by Myriad Genetic Laboratories, Inc. as part of TheraGuide 5-FU test. DNA was extracted and purified from white blood cells. Genetic variants within pt's DPYD were detected by comparison with a consensus wild-type DPYD sequence. Results: Among 227 pts from toxicity group 27 (12%) had deleterious mutations in DPYD: 12 (5%) had IVS14 +1 G>A, 11 (5%) had D949V and 4 (2%) other mutations. Only 7/192 (4%) pts from control group had DPYD genotype abnormalities: 2 (1%) had IVS14 +1 G>A, 4 (2%) had D949V and 1 (1%) other mutation. Genotype abnormalities were seen more frequently in toxicity group (p=0.001). Among 49 pts with HFS 9/49 (18%) had mutated DPYD. 9/46 (20%) pts with myelosupression were found to have a deleterious mutation. Mutations were more frequent in both subgroups when compared to control group: p=0.001 and 0.0007 respectively. Among 65 pts with toxicities due to CAP 9 (14%) had mutated DPYD which was more frequent than in control group (p=0.006). Conclusions: Mutated DPYD is frequently observed in Caucasian pts who experience toxicities while receiving 5-FU/CAP. Screening pts for DPYD mutations prior to administration of 5-FU/CAP using new pharmacogenetic testing methods may help to identify those pts who are at greatest risk for adverse effects, allowing a more individualized approach to their chemotherapy management. [Table: see text]
Small molecule pan-bcl-2 inhibitor AT-101 induces apoptosis in NSCLC by up-regulating noxa and enhances antitumor activity of docetaxel or targeted kinase inhibitors
Authors: Min P. , Zhang Y. , Ni X. , Wang H. , Wang J. , Wang G. , Leopold L. , Sorensen M. , Yang D. 
Published: August 2020

e14591 Background: AT-101 is an orally active pan Bcl-2 inhibitor currently under clinical development in Phase II trials. We investigated the effect of AT-101 alone or in combination with chemotherapies or targeted kinase inhibitors in NSCLC both in vitro and in vivo. Methods: Growth inhibition was measured by WST assays. The CalculSyn method was used to assess drug interaction by calculating the Combination Index (CI) value. The ability of AT-101 to potentiate the anti-cancer effect of chemotherapies or kinase inhibitors was evaluated in xenograft models. Results: A panel of 11 NSCLC cell lines with overexpression of Bcl-2, Bcl- XL or Mcl-1 proteins was treated with AT-101, docetaxel, pemetrexed, erlotinib, sorafenib, sunitinib, rapamycin, as a single agent and in combination. AT-101 inhibited the growth with IC50 at 3–9 uM. When treating cells simultaneously with both agents, AT-101 demonstrated strong synergy with those agents in A549 or H460 cells with CI values < 1.0. Protein analysis results indicated that AT-101 caused apoptosis by a time- and dose-dependent induction of Noxa expression in those cells. The expression of Bcl- XL was not influenced by AT-101. Pro-Caspase-3 was reduced with increasing doses of AT-101. In vivo, combined treatment of AT-101 with docetaxel, erlotinib, or sorafenib synergistically suppressed subcutaneous NSCLC A549 cells tumor growth compared with treatment with either agent alone. The synergist effects with the ErbB1 inhibitor Erlotinib is associated with the overexpression of the target protein ErbB1 in those cells. Only combination therapy resulted in significant tumor growth delay and no significant toxicities were observed. Conclusions: Our results demonstrate that AT-101significantly enhances the anti-tumor activity of chemotherapy and targeted agents and may represent a promising new anticancer agent with a novel molecular mechanism. Molecular targeted therapy with AT-101 may improve the outcome of current chemotherapy for NSCLC with Bcl-2, Bcl-xL and/or Mcl-1 overexpression. [Table: see text]
Effect of GM-CSF on tumor-specific immune response and antitumoral efficacy when combined with suicide gene therapy
Authors: Akbulut H. , Coleri A. , Acikgoz N. , Sahin G. , Ozkal P. , Tang Y. , Icli F. , Deisseroth A. 
Published: August 2020

e14610 Background: Suicide gene therapy is one of the promising treatment modalities in cancer treatment. Combination of an immunotherapy modality with suicide gene therapy would increase the tumor eradciating efficacy of either treatment strategy used alone. Methods: In the current study, we constructed adenoviral vectors carying ytosine deaminase (CD), granulocyte macrophage-colony stimulating factor (GM-CSF) vectors. We tested the in vitro efficacy of the vectors in both human and mouse tumor cell lines and in a syngeneic mouse model of colon cancer with tumor explants of CRL 2638 cells. Results: Our results show that the vectors carrying CD/GM-CSF transcription units are effective in terms of killing of tumor cells when 5-FC added. Addition of GM-CSF transgene induced a significant amount of GM-CSF secretion (250 pg/ml/105 cells) of infected cells. In the syngeneic colon cancer model, addition of GM-CSF significantly increased tumor-specific cellular immune response when compared to suicide gene therapy alone. (p<0.01). Likewise, GM-CSF addition caused a 8 times reduction in the ratio of Tregs infiltrating the tumor nodules (p<0.001). Accordingly, GM-CSF decreased the tumor growth by 2 times an d increased the median survival time by 50% (p<0.01). Conclusions: These impressive results of in-vitro cytotoxicity and encouraging results of in-vivo testing of the our newly constructed GM-CSF carrying vector suggest a potential for the use of the vector for the treament of established tumors by inducing tumor specific immune response. No significant financial relationships to disclose.
Inhibition by lenalidomide of growth factor and hypoxia-induced signaling in endothelial and epithelial tumor cells, and effects within the tumor cell microenvironment
Authors: Lu L. , Schafer P. , Bartlett J. B. 
Published: August 2020

e14620 Background: Lenalidomide, an immunomodulatory and anti-angiogenic agent, has activity in many hematological malignancies. It has direct anti-proliferative activity in hematological cells but there is no evidence of direct activity in solid tumor cells. In solid tumors, lenalidomide is being advanced in combination with other agents to take advantage of its immune-enhancing properties in combination with direct anti-tumor agents. Lenalidomide studies in CLL and MM suggest that it may also attenuate pro-survival signals generated by interaction of stroma with the malignant cell itself. Lysophosphatidic acid (LPA) is a key pro-survival factor present at high levels within the ascites of ovarian cancer patients which confers increased tumor invasiveness and reduced survival. Hypoxia-induced factor (HIF)-1α is the key initiator of angiogenesis and tumor invasiveness. Methods: The effect of lenalidomide on growth factor-induced Akt phosphorylation was investigated in endothelial cells, NHL cells, and ovarian cancer cells in vitro. Ovarian cancer cell lines SKOV-3 and OVCAR-3 were treated with LPA and the effect of lenalidomide on invasiveness via enhanced p-Akt was investigated. The effect of lenalidomide on HIF-1α expression by endothelial cells and epithelial cells was also investigated. Results: Lenalidomide inhibited growth factor-induced Akt phosphorylation. Treatment of ovarian tumor cells with LPA increased tumor cell invasiveness via enhanced p-Akt. Lenalidomide strongly inhibited invasion and p-Akt (at S308 but not T473) in a dose-dependent manner. Hypoxic endothelial cells and epithelial tumor cells showed enhanced HIF-1α expression. Lenalidomide inhibited hypoxia-induced HIF-1α expression by endothelial cells and by epithelial tumor cells, including prostate, breast, pancreatic, renal and ovarian tumor cells. Conclusions: Lenalidomide may act within the tumor microenvironment to inhibit key signals of tumor cells survival, growth, and invasiveness. These studies support the potential utility of lenalidomide in combination with other agents in the treatment of patients with solid tumors. [Table: see text]
Inhibition of Notch and tumor regression
Authors: Epenetos A. A. , Kousparou C. , Stylianou S. 
Published: August 2020

e14623 Background: Notch signaling is an evolutionary-conserved pathway in vertebrates and invertebrates which is involved many developmental processes, including cell fate decisions, apoptosis, proliferation, and stem-cell self renewal. There is increasing evidence that the same molecular pathways regulating the self renewal of stem cells are also being employed in cancer progression. The Notch signal transduction pathway has been implicated in the self-renewal of stem cells in hematopoietic, skin, neural, germ and breast tissue. Increasing evidence suggests that the Notch signaling pathway is frequently up regulated in many forms of cancer including acute T-cell lymphoblastic leukemia, cervical, prostate, lung, breast and others. Thus,inhibition of the pathway could provide a novel treatment of cancer and cancer stem cells. Methods: We have genetically engineered a fusion protein, consisting of the Drosophila transcription factor Antennapedia (ANTP) and with the truncated version of Mastermind-like (MAML) that behaves in a dominant negative (DN) fashion and inhibits Notch activation (ANTP/DN MAML, TR4). This novel fusion protein has been tested for its ability to target tumor cells in vitro and in vivo. Results: Our data show that ANTP/DN MAML fusion protein, TR4 contains signals for proper cell targeting, internalization and nuclear transport. Furthermore, TR4 inhibits human mammary and colon xenograft tumor growth and metastases in immuno deficient mice.TR4 presence and activity was also detected in the brains of treated animals demonstrating that TR4 can cross the blood-brain barrier and potentially eliminate brain tumors and metastases, unlike other anticancer drugs and biological such as monoclonal antibodies that cannot cross the blood brain barrier. TR4 was found to be non- immunogenic following repeat administration in healthy animals. At very high doses (>10x therapeutic dose) it caused anorexia and weight loss in mice. Conclusions: The TR4 protein, a Notch inhibitor, can induce tumor regression and resolution of breast and colon cancer xenografts. It is non- immunogenic following repeat administration and has acceptable toxicity profile. No significant financial relationships to disclose.