bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unlocking PARP inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform.
Authors: Bindra Ranjit , Sundaram Ranjini K , Aiello Robert J , Marshall Dan , Bourassa Patricia , Csengery Johanna , Zhang Qing , Robinson Brett , lopresti-Morrow Lori , Bechtold Jane , Tylaska Laurie , Paradis Tim , Paralkar Vishwas , Hellsund Per , Glazer Peter 
Published: May 2019

e14664 Background: Poly(ADP-ribose)polymerase inhibitors (PARPi’s) are a promising new class of anti-cancer agents, but their clinical application has largely been limited to tumors with homologous recombination deficiency (HRD), such as those with BRCA1/2 mutations. One strategy to target HRD-negative tumors with PARPi’s is to combine them with chemotherapy, although clinical trials indicate that dose-limiting toxicities are a major barrier to achieving synergistic efficacy with these combinations. Methods: We sought to test the hypothesis that HRD-negative cancers can be effectively treated with tumor-targeted PARPi’s in combination with chemotherapy, using our recently developed alphalex platform. This platform allows small molecule anti-cancer agents to penetrate cell membranes only at the low pH associated with the tumor microenvironment and tumor cells, directly delivering drugs to tumors while sparing normal tissue. We tested whether alphalex PARPi-conjugates in combination with chemotherapy could selectively kill cancers independent of HRD status, using a range of in vitro and in vivo tumor models. Results: We conjugated a diverse range of structurally unique PARPi’s using the alphalex platform, and demonstrated that these molecules are delivered directly into tumor cells in a pH-dependent manner. We observed significant reductions in PARylation activity and exquisite synergy with DNA damaging agents in vitro. We then demonstrated that alphalex-PARPi conjugates in combination with both temozolomide (TMZ) and irinotecan induce significant tumor cell killing in HRD-negative tumors in vivo. Importantly, we found that our tumor-targeting approach significantly reduced normal tissue toxicity, with almost complete sparing of the bone marrow relative to TMZ alone. Conclusions: The alphalex platform enables PARPi combinations with clinically relevant chemotherapies, as a means to target HRD-negative cancers without significant bone marrow toxicity. Based on these successful proof-of-concept data, we are now performing IND-enabling studies for an alphalex PARPi conjugate (CBX-11), and we anticipate initiating a Phase I clinical trial in January 2020 in solid tumors independent of HRD status.
A general approach to optimizing tumor treating fields therapy.
Authors: Bomzon Zeev , Urman Noa , Hershkovich Hadas Sara , Kirson Eilon David , Naveh Ariel , Shamir Reuven , Federov Eduard , Wenger Cornelia , Weinberg Uri 
Published: May 2019

e14668 Background: Tumor Treating Fields (TTFields) are alternating electric fields used to non-invasively treat cancer. TTFields are delivered via transducer arrays placed on the skin close to the tumor. Post-hoc analysis [1] has shown that delivering higher field power to the tumor and increasing usage (percent of time patient is actively treated) improve patient survival. Thus, optimizing the position of arrays to maximize TTFields power at the tumor could improve survival. At the same time, minimizing the array area to maximize patient comfort and consequently maximizing usage is also likely to improve survival. However, optimizing TTFields delivery is non-trivial since the field distribution is influenced by array positioning and geometry, the anatomy of the patient and the heterogeneous electric properties of different tissues. Here we present a general approach to optimizing Tumor Treating Fields using numerical simulations. Methods: Delivery of TTFields to the brains, lungs and abdomens of realistic computational models was investigated. The effect of the transducer array size and position on the field distribution within the phantoms was analyzed, and an approach for optimizing TTFields delivery developed. Results: Field power is generally highest in the region between the arrays, with larger arrays generally delivering higher field power. Anatomical features such as bones, the spine or a resection cavity significantly influence the field within this region. A general approach to optimizing TTFields delivery is: Maximize field power by using the largest arrays possible. To maximize patient comfort, array size are chose so that significant portions of the skin in the region of disease are not covered by the arrays. Place virtual arrays on a realistic computational model of the patient such that the tumor is located between them and simulate TTFields delivery to the patient. Apply an iterative algorithm to shift the arrays around their initial positions until field power in the tumor bed is maximized. Conclusions: We have developed a general approach to optimizing delivery of TTFields to the tumor. Effective TTFields treatment planning is expected to improve patient outcome. [1] Ballo et. al., submitted to RED Journal 2018.
ABT-806 derived antibody drug conjugates (ADCs) inhibit growth of malignant mesothelioma in-vivo.
Authors: Chia Puey Ling , Cao Diana , Gan Hui Kong , Reilly Edward B. , Phillips Andrew , John Thomas , Scott Andrew Mark 
Published: May 2019

e14677 Background: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%. We have investigated an anti-EGFR antibody (ABT-806), which is tumor specific and robustly inhibits EGFR-expressing tumors. We have previously shown that ABT-806 ADCs demonstrate potent anti-tumor activity in 806 immunohistochemistry (IHC) positive MSTO-211H MM cell line xenograft model. We present data in MM using ABT-806 novel ADCs [ABT-414 (ABT-806- monomethyl auristatin F), ABBV-221 (ABT-806- monomethyl auristatin E) and ABBV-321 (ABT-806- pyrrolobenzodiazepine)] in MM patient derived xenografts (PDX). Methods: We evaluated expression of EGFR and mAb 806 IHC in MM cell lines and PDXs. PDXs were implanted into 5 to 10 NOD-Scid mice per group and treated with control ADC, saline, cisplatin or ABT-806 ADCs and followed longitudinally with caliper measurements. Comparative statistics were performed in Graphpad prism. Results: Three PDX models were selected according to their 806 IHC statuses (2 epithelioid 806 IHC positive, 1 biphasic histology 806 IHC negative). In one epithelioid PDX model, ABBV-321 resulted in significantly reduced tumor growth on day 27 post therapy with median tumor volumes of 180 mm3 (ADC control) compared with 78mm3 (ABBV-321; p = 0.0159 two-sided). Moreover, the median survival was also significantly longer in ABBV-321 treated models (p = 0.018). In the other epithelioid PDX model, ABBV-321 also resulted in significant responses (median 428mm3 (ADC control) vs 167mm3 (ABBV-321, p = 0.0201). In the 806 IHC negative PDX model, the differences in tumor volumes between all groups were found to be non-statistically significant (ADC control vs ABT-414, ADC control vs ABBV-221, ADC-control vs ABBV-321 groups) with p = 0.0597 for one-way ANOVA. MSTO211H cell line xenograft model also demonstrated significant anti-tumor response to both ABT-414 and ABBV-221 (p < 0.01). Conclusions: In a disease with limited therapies, ABT-806 targeting ADCs in MM demonstrated significant responses in 806+ PDX and cell lines. These data support clinical expansion of these compounds in 806+ MM patients.
TrkA neurotrophin receptor and PI3K-Akt signaling involvement in cranial irradiation-induced memory deficit.
Authors: Ji Shengjun , Yang Ming , Yu Jinming 
Published: May 2019

e14679 Background: This study aimed to investigate the role of neurotrophin receptor TrkA in cranial radiation-induced memory decline. Methods: Single dose of 10Gy 4MeV electron beam whole brain irradiation (WBI) was given to young male Sprague-Dawley rats (50–60g, day 21). 3 months after WBI, western blot was performed to detect protein level of TrkA and its downstream signaling molecules. The Morris water maze test was performed to evaluate the consequence of WBI on hippocampus-dependent memory formation. Immunohistochemistry was performed to evaluate the consequence of WBI on neurogenesis. For overexpression of TrkA, Adeno-associated virus were injected at the rate of 0.2μl/min (n = 15-20 per group). After that, Morris water maze test was performed again. Results: In Morris water maze test, WBI lead to notable memory deficit, the irradiation rats spent longer latency time than control rats (p < 0.05). In the spatial probe trial, the irradiation rats spent less time in the target quadrant than control rats (p < 0.05). Immunohistochemistry showed that cranial irradiation inhibited proliferation and neurogenesis in hippocampus. The protein level of TrkA expression decreased significantly at 3 months after irradiation compared with control group. Phosphorylation of PI3k, AKT, ERK1/2, CREB were also observed to be significantly inhibited (all p < 0.05). Next, we explored the irradiation-induced apoptotic signal transduction. The increased expression of JNK, caspase-3/9 and reduced expression of BCl2 confirm the irradiation induced apoptosis. After Adeno-associated virus injection, AAV-overexpression TrkA rats showed less escape latency time (p < 0.05) and spent more time (p < 0.05) in the target quadrant than AAV-irradiation rats, but still more escape latency time (p < 0.05) and spent less time (p < 0.05) in the target quadrant than AAV-control rats. Additionally, immunofluorescence staining showed AAV-overexpression-TrkA also rescued radiation-induced neurogenesis impairment Conclusions: TrkA may play a critical role in radiation-induced memory deficit, which indicate the data may have important therapeutic implications.
The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients.
Authors: Zhu Hong , Lin Quan , LI Yuping , Zhang Haoran , Ding Huaxin , Han-Zhang Han , Lin Jing , Xiang Jianxing 
Published: May 2019

e14681 Background: BRAF mutations, occurring in 2-4% NSCLC patients, can be classified into 3 classes based on signaling mechanism and kinase activity: V600-mutant RAS-independent kinase activating monomers (class I), RAS-independent kinase activating dimers (class II) and RAS-dependent kinase inactivating heterodimers (class III). The association between functional classes and clinical features of Chinese NSCLC patients remain elusive. Methods: Sequencing data of either plasma or tissue samples obtained from 8,405 Chinese (Stage I-IV NSCLC) patients were retrospectively analyzed to screen for BRAF mutations. Of the patients with BRAF mutations, 79% (188/238) were diagnosed with adenocarcinoma,7.6% with squamous cell carcinomas (SCC) and the remaining patients were either adenosquamous carcinoma or large cell carcinoma. Results: BRAF mutations were detected in 238 patients, revealing a prevalence of 2.8%. Among them, 32% (75/238), 21% (51/238) and 13% (31/238) had class I, II and III mutations, respectively. The remaining 35% (81/238) had other BRAF mutations. V600 (32%, 75/238) and G469 (13%, 32/238) were the 2 most predominant mutations. BRAF mutations, when considered collectively, including non-class I-III mutations, were more likely to occur in males ( p< 0.01). However, class I mutations have a female predominance (p = 0.003); whereas, class II mutations showed a trend of male predominance (p = 0.09) and class III had no gender preference (p = 0.22). We also revealed no association between histology types and the class of BRAF mutations. Next, we investigated co-occurring classic lung cancer driver mutations in this cohort and revealed that patients with class II and III mutations were more likely to have concurrent KRAS mutations (p = 0.001). We also compared the overall survival (OS) of chemotherapy-treated patients and revealed comparable OS among the 3 groups. Conclusions: Our study revealed a 2.8% BRAF mutation rate in Chinese NSCLC patients. Our data also showed a male predominance when all BRAF mutations were considered collectively, and a female predominance for class I mutations. Furthermore, patients with BRAF V600E is less likely to have concurrent KRAS mutations.
The role of anticoagulants for the primary prophylaxis of venous thromboembolism in patients with malignancy: A systematic review and meta-analysis of randomized controlled trials.
Authors: Barbarawi Mahmoud , Zayed Yazan , Kheiri Babikir , Gakhal Inderdeep , Barbarawi Owais , Bala Areeg , Alabdouh Ahmad , Abdalla Ahmed , Haykal Tarek , Goranta Sowmya , Bachuwa Ghassan , Katato Khalil 
Published: May 2019

e14691 Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Despite this, pharmacologic prophylaxis for the primary prevention of VTE is not offered for most medical oncology patients, likely due to the competing risk of bleeding. Recent trials may offer new insight into the role of anticoagulants for the prevention of cancer associated thrombosis (CAT). Accordingly, we conducted a meta-analysis of randomized controlled trials (RCTs) that evaluated anticoagulants for the primary prophylaxis of VTE in cancer patients. Methods: A literature search of Pubmed/MEDLINE, Embase, and Cochrane library was done by two investigators. All RCTs that used anticoagulant in cancer patients for primary prevention of VTE were included. The primary outcomes were VTE events and all-cause mortality; VTE related mortality and major bleeding were secondary outcomes. A random effects model was used to report the risk ratios (RR) with 95% confidence intervals (CIs), and odds ratios (ORs) with Bayesian 95% credible intervals for both direct and network meta-analysis, respectively. Results: Twenty-four RCTs were included with a total of 13,338 patients (7,197 received anticoagulants and 6,141 received placebo). Of these trials, 19 used low-molecular weight heparin (LMWH), 3 used direct oral anticoagulants (DOACs), 2 used warfarin, and 1 used heparin. Mean age ranged between 54.6 to 68.1 years, with 50.5% male. Compared with placebo, LMWH or DOACs were associated with reduced VTE events (RR 0.58; 95% CI 0.48-0.69, p < 0.001) and (RR 0.39; 95% CI 0.24-0.63, p < 0.001), respectively. LMWH compared with placebo was associated with decreased VTE, and all-cause mortality (P < 0.05). While DOACs was associated with decreased PE events only compared with placebo (RR 0.28; 95% CI 0.11-0.71, P = 0.008). Regarding the safety outcome, LMWH and DOACs were associated with an increased risk of major bleeding compared with placebo, but this did not reach statistical significance in this study (RR 1.26; 95% CI 0.92-1.74, p = 0.16 and RR 1.76; 95% CI 0.83-3.73, p = 0.14). Results regarding VTE events and major bleeding were consistent in both lung and pancreatic cancers. Conclusions: Both LMWH and DOACs were associated with a lower number of VTE events compared with placebo. However, this potentially protective effect must be balanced against a possible increased risk of bleeding for some patients.
Direct oral anticoagulants (DOAC) versus warfarin and enoxaparin in ovarian vein thrombosis.
Authors: Covut Fahrettin , Kewan Tariq Zuheir , Perez Oscar , Awada Hassan , Babar Arslan , Thapa Bicky , Haddad Abdo S. , Spiro Timothy Peter , Daw Hamed 
Published: May 2019

e14698 Background: Ovarian vein thrombosis (OVT) is a rare condition that is commonly associated with malignancy. Efficacy and safety profile of DOAC in OVT has not been compared with warfarin and low-molecular-weight-heparin in the literature. Methods: We reviewed patients who were diagnosed with OVT between 11/2012 and 1/2018 and had follow-up imaging with computed tomography to assess resolution of thrombus. The outcomes of interests were thrombus resolution, recurrent thromboembolic events, and 1-year cumulative incidence of clinically significant bleeding events. Cumulative incidence was calculated with death and discontinuation of therapeutic anticoagulation as competing risks. Results: We identified 36 patients, 17 (47%) had right, 14 (39%) had left, and 5 (14%) had bilateral OVT. Median age and body mass index at diagnosis were 47 (range: 25 - 86) and 28 (range: 19 – 43), respectively. At least one predisposing factor was identified for 32 (92%) patients, 16 (44%) had underlying active malignancy. Overall, 27 (75%) patients achieved complete or partial recanalization at follow up CT after median of 4 months (range: 1 – 13) from initiation of anticoagulation. Ten (28%) and 11 (31%) patients were treated with DOAC and warfarin after median of 3 and 2 days of anticoagulation with unfractionated heparin or enoxaparin, and follow up CT after median of 6 and 4 months showed complete/partial recanalization rates of 70% and 55%, respectively (p = 0.47). Whereas, 15 patients received enoxaparin and follow up CT after median of 3 months showed that 93% of patients achieved complete/partial recanalization (p = 0.12 between DOAC vs enoxaparin cohorts). Recurrent thromboembolic event has not occurred in any patient during median follow-up of 14 months (range: 3 – 71). One-year cumulative incidence of clinically significant any bleeding for DOAC cohort versus warfarin and enoxaparin cohorts was 10% (95% CI: 9 – 28) versus 18% (95% CI: 12 – 41), p = 0.64, and 25% (95% CI: 4 – 46), p = 0.42, respectively. Conclusions: Apixaban and rivaroxaban showed similar risk-benefit ratio as warfarin and enoxaparin, hence, they can be considered as alternatives for OVT patients.
Changes of estrogen receptor, progesterone receptor and HER2 expression in breast cancer with/without neoadjuvant chemotherapy or endocrine therapy.
Authors: Maeda Shigeto 
Published: May 2019

e14699 Background: Concordance in hormone receptor and Human Epidermal Growth Factor Type 2 (HER2) status in breast cancer was observed between initial biopsy and surgical specimens. This study aimed to analyze the correlation in Estrogen receptor (ER), Progesterone receptor (PR) and HER2 status of the initial biopsy and surgical specimen in non-neoadjuvant therapy (CON), neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NAE). Secondary aim is to know the changed expression of ER, PR and HER2 as predictive marker for overall survival. Methods: We retrospectively analyzed 1265 surgical specimens from April 2007 to January 2018 in National Nagasaki Medical Center. Out of 1265 patients, 752 CON, 144 NAC and 28 NAE pairs of samples from initial core biopsy and surgical specimen were compared to the expression of the ER, PR and HER2 by immunohistochemically. Spearman’s rank correlation coefficient is calculated. Results: See table. Conclusions: ER and PR expression percentage is highly correlated between core needle biopsy and surgical specimen. After neoadjuvant chemotherapy, PR lost 8.2% after NAC and 40.8% after NAE. PR loss may become predictive marker after systemic therapy.[Table: see text][Table: see text]
Modulating the tumor microenvironment to enhance efficacy of PARP inhibitors.
Authors: Mehibel Manal , Xu Jimmy , Diep Anh , Thakkar Kaushik , Li Caiyun G , Xiao Yiren , Rankin Erinn , Giaccia Amato 
Published: May 2019

e14715 Background: PARP inhibitors (PARPi) have demonstrated activity in HR deficient tumors through synthetic lethality. However, their clinical efficacy has not been highly promising, with response rates ranging between 30-60% for Olaparib, Talazoparib and Veliparib (1). This highlights the necessity to understand the mechanisms of resistance and how these agents work in the context of the tumor microenvironment. In this study, we explore the effect of hypoxia on the efficacy of PARPi in a range of HR-deficient tumors. Hypoxia is known to downregulate genes of homologous recombination (2) but its role in HR deficiency in still unknown. Methods: HR deficient tumor cell lines were treated with PARPi under both aerobic and hypoxic conditions. DNA damage markers such as γH2AX, 53BP1 and RIF1 were detected by immunofluorescence. Tumor xenografts were grown to 100 mm3 prior to treatment with vehicle, PARPi, hypoxia activated cytotoxin, or the combination and tumor volumes were measured. Co-localization of apoptosis and hypoxia was detected by IHC. Finally, hypoxic signature in breast PDX models was correlated with their sensitivity to PARPi. Results: We found that hypoxic cells are significantly more resistant to PARPi in cell culture models. Efficiency of inhibition of PARP activity by these agents was similar under both air and hypoxia. The DNA damage marker γH2AX increased in cells treated in air, but not under hypoxia. There was no loss of 53BP1 protein that regulate engagement of the c-NHEJ pathway, indicating that HR has not been restored in these cells (3). However, it’s binding partner RIF1 was lost in hypoxia upon treatment indicating deficient signaling downstream of 53BP1. RIF1 is known to inhibit 5’ resection and its loss leads to resistance to PARPi in BRCA-deficient cells (4). In vivo, combining PARPi with hypoxia activated prodrugs led to substantial tumor growth delay in three xenograft models. DNA damage and apoptosis in these tumors was only detected outside of hypoxic regions positive for pimonidazole. In the breast PDX models, there was a strong correlation between the level of hypoxia in these tumors and their sensitivity to Olaparib. Conclusions: The significant increase in anti-tumor effects with the combination of PARPi and hypoxia-targeting cytotoxins leads us to propose a new strategy for tumors which are not responsive to PARPi alone. 1. Brown JS et al. Br J cancer 2016, 114, 713-5 2. Chan N et al. Cancer Res 2010, 70,8045-54 3. Bunting SF et al. Cell 2010, 141, 243-54 4. Chapman JR et al. Mol Cell 2013, 49, 858-71.