bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of telotristat ethyl: A peripheral tryptophan hydroxylase inhibitor that blocks serotonin biosynthesis against cultured liposarcoma, colon cancer, and cholangiocarcinoma cell lines.
Authors: Kliman Harvey J. , Ling Ivy S , Milano Kristin M
Published: May 2020

e15602

Background: Serotonin (5-HT) is most often considered a neurotransmitter—but in reality its main function is to promote cell proliferation at the site of wound healing via platelet degranulation. We tested the hypothesis that blocking 5-HT production in cancer cells might lead to their death by exposure to a specific tryptophan hydroxylase (TPH) inhibitor: telotristat ethyl (TE). The advantage of this TPH inhibitor is that it does not cross the blood brain barrier and therefore can be used to treat peripheral cancers without danger of interfering with central nervous system 5-HT production. Methods: Three cancer cell lines were tested: liposarcoma (94T778), colon cancer (HT-29), and cholangiocarcinoma (TFK-1). The cells were grown with 0, 5, 15 and 30 µM TE, plated into four-chambered slides with an initial confluence of at least 30%, and cultured for 24-96 H. At the end of each 24 hour period slides were removed, washed, fixed, and stained with hematoxylin for density assessment. Experiments were performed in triplicate and repeated in at least three separate experiments. Cell confluence was determined under low power microscopic examination. Results: In the absence of TE the three cell lines increased their confluence from approximately 30% to 83±5.8% (94T778), 68±11% (HT-29), and 60±16% (TFK-1) over 96 H. When the 94T778 cells were exposed to increasing concentrations of TE their confluence decreased progressively. At a dose of 30 µM cell confluence at 24 H was 3±0%, at 48 H 0.3±0.6%, at 72 H 0±0%, and at 96 H 0±0%. For the HT-29 cells, cell confluence in the 30 µM TE groups were 12±8%, 3±3%, 7±5% and 2±1% at 24, 48, 72 and 96 H, respectively. For the TFK-1cells, cell confluence in the 30 µM TE groups were 7±3%, 20±14%, 17±14% and 24±16% at 24, 48, 72 and 96 H, respectively. Conclusions: Telotristat ethyl is a potent inhibitor of tumor cell line growth. However, the efficacy of this inhibition varies between cell lines. The liposarcoma cell line was most sensitive to TE, with the cholangiocarcinoma cell line being moderately impacted. The colon cancer cell line was intermediate between these two. The differences in response to TE may be related to the specific expression of TPH in any particular cell line, with cancers that are more dependent on 5-HT production being most impacted by TPH blockade. Just as ER PR positive breast cancers are sensitive to blockade of these receptors, TPH positive cancers may be successfully targeted by specific inhibition of the 5-HT biosynthetic pathway.
EIT PACMAN Study preliminary results: OncoSignal pathway analysis identifies actionable cancer targets.
Authors: Martin Patricia , Neerken Sigi , Van De Stolpe Anja , den Biezen-Timmermans Eveline , Akse Martijn , Ngocamus Maud , Nicotra Claudio , Eggermont Alexander M. , Van De Wiel Paul , Massard Christophe , Calvo Fabien M.
Published: May 2020

e15606

Background: Precision medicine refers to tailoring of treatment to each individual patient, although identifying tumor driving signaling pathways (SP) that are functionally active is still a challenge. OncoSignal pathway tests quantitatively measure activity of SP such as estrogen receptor (ER), androgen receptor (AR), PI3K, MAPK, Hedgehog (HH), TGF-β, Notch on fresh frozen and formalin-fixed paraffin-embedded (FFPE) tissue samples. OncoSignal pathway analysis aimed at assessing clinically actionable SP and retrospectively predicting targeted drug response on a series of patients’ (pts) samples from the MOSCATO trial run at Gustave Roussy. Methods: OncoSignal pathway analysis (ER, AR, PI3K, MAPK, HH, Notch, TGF-β) was performed blinded by Molecular Pathway Dx (Philips, Eindhoven) on metastatic tumor tissue samples from breast cancer (BC), prostate (PC), and high grade serous ovarian cancers (OC). Using Affymetrix expression array data from public GEO datasets, SP activity was analyzed in healthy prostate, breast, and ovarian tissue to define abnormal SP activity thresholds for tumor tissue pathway analysis. For each individual sample, SP alterations were considered tumor driving SP if sample SP activity exceeded the 95th percentile of SP activity within healthy tissue. Results by OncoSignal were also combined with clinical characteristics and molecular alterations identified in the MOSCATO trial. Results: Identified tumor driving SP were ER, AR, MAPK-AP1, HH, PI3K pathway in BC (n = 5), AR in PC (n = 30); AP1, Notch, TGFβ in OC (n = 17). OncoSignal identified clinically actionable tumor driving pathways in all BC samples (median tumor cellularity [MTC]: 40%, range 15-80%); 30/31 PC samples (MTC: 62%, range 25-90%), 16/17 OC samples (MTC 62%, range 15-80%). Actionable mutations were previously identified in 4/5 BC; 13/31 PC; 6/17 OC. Seven pts with BC and PC were treated with targeted therapy. OncoSignal pathway analysis correctly predicted response/resistance in 4 of these pts (57%). Conclusions: OncoSignal pathway analysis correctly identified SP activity alterations and predicted targeted drug response in this series of patients. OncoSignal will be further validated prospectively in precision medicine studies at Gustave Roussy in which patients are stratified for targeted treatment by mutation analysis.
Role of tafamidis in reducing the effect and progression of transthyretin amyloid cardiomyopathy.
Authors: Konda Raghunandan , Vadala David , Rafae Abdul , Isa Sakiru , Devarkonda Vishal , Kesari Kavitha , Kunadi Arvind
Published: May 2020

e15612

Background: Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a rare, life-threatening, progressive and underdiagnosed cause of restrictive cardiomyopathy and heart failure. ATTR-CM is a type of cardiac amyloidosis caused due to misfolded and destabilized transthyretin amyloid protein deposits in the myocardium. Tafamidis is a transthyretin (TTR) modifying targeted drug that stabilizes and prevents tetramer dissociation and amyloid deposits. Our aim is to conduct a review of literature to determine the effect of tafamidis on the structural progression of transthyretin cardiomyopathy while also looking into all-cause mortality outcomes. Methods: A systematic search was performed in PubMed, Embase, and Cochrane using the MESH terms "Tafamidis" and “Transthyretin Amyloid cardiomyopathy.” Two authors independently reviewed article titles and abstracts. Disagreements were resolved by consensus and then adjudicated by a third author. All articles published in English up to the year 2019 were eligible for inclusion. Data was tabulated and analyzed. Studies measuring mortality outcomes and echocardiogram findings with the use tafamidis in ATTR-CM were included. Studies that did not measure mortality outcomes were excluded as well as case reports and animal studies. Results: Out of the studies identified through databases (n = 57), only 6 studies met the inclusion criteria as earlier studies delved strictly into the tolerability and safety of the drug. The studies that were included in this analysis are heterogeneous, because ATTR-CM is phenotypically heterogeneous (wild type-ATTR-CM or mutant ATTR-CM) and has varying degrees of amyloid deposits and cardiac symptoms. The role of tafamidis in reducing the effect of cardiomyopathy in transthyretin amyloid cardiomyopathy is unclear. Effects on the structural changes of the myocardium including the ejection fraction remain inconsistent. A recent multicenter, international, phase 3 randomized controlled trial shows reduction in all-cause mortality comparing tafamidis vs placebo. (29.5% vs 42.9%). Conclusions: With the recent approval of tafamidis, it is vital to review and analyze the available data to study its effects on transthyretin amyloid cardiomyopathy. While structural improvements with tafamidis therapy are inconsistent, reduction in all-cause mortality with this novel drug is promising.
Efficiency: Minimizing dose escalation steps by calculating human dosing preclinically.
Authors: Gyorffy Steve , Blunt Al , Messerschmidt Gerald L.
Published: May 2020

e15622

Background: Historically, oncology drug development can take years to accomplish the goal of bringing new agents to patients. Scientific knowledge is evolving rapidly, transforming our understanding of the diseases at a rapid pace. This necessitates expedited drug development and approval to allow benefit for cancer patients. First-in-human administration to accelerated approval worthy data can efficiently occur in approximately two years, often in small very specific populations (individualized [precision medicine] therapy). The pre-clinical time period solidifies basic knowledge of mechanism of action, dosing, schedule, safety and efficacy both in vitroand in vivo, but adds to the development timeline of these products. Determining the correct dose has been identified by us and others as a critical issue that often leads to prolonged Phase 1 dose escalation in very expensive human testing environments.To optimize development timelines, we have targeted identification of dose (safe vs toxic and no benefit vs effective) as a critical area to define in these pre-clinical experiments. Methods: Tumor cell killing concentrations are essential to understanding the required lower limits and optimal amounts of drug available at the target cell (cancer or immune cell), with cognizant regard to toxicity in normal tissue, both a key focus of preclinical testing. Determining these concentrations in vivo are important data sources for this concept of “therapeutic index”. Defining the concentration for killing range and concentrations in total body water can then be used to calculate human starting dose that is within or near the beneficial anti-cancer concentration, but not at the predicted toxic concentration for normal human tissues. Results: By using a mathematical algorithm, we have developed a set of formula’s that can translate micro-molar or similar concentrations in vitro, and animal studies to human optimized dose escalation trials. This often involves predicting maximum tolerated dose (MTD) or optimal biologic dosing (OBD) for efficacy and safety rather than forcing the appearance of Dose Limiting Toxicities (DLT). Conclusions: This pre-clinical work has the potential to be able to decrease the in-human dose escalation time period and lead to more efficient development of novel therapeutics.
OSU-03012 induces apoptosis of gastric cancer cells through endoplasmic reticulum stress triggered inhibition of Akt and STAT3 signaling pathways.
Authors: Peng Wei , Xu Xia , Chen Xiaoxiang , Feng Jifeng , Shen Bo , Lu Jianwei
Published: May 2020

e15630

Background: As the chemotherapeutic resistance and postoperative relapse rates of gastric cancer rise year by year, searching for novel chemoprevention compounds has become fairly imminent. 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide (OSU-03012), a derivative of anti-inflammatory drug celecoxib, has recently been shown to have anti-tumor effects. But its roles and underling mechanisms in gastric cancer is rather unknown. Methods: In this study, we show for the first time that OSU-03012 inhibits the growth and potently induces the apoptosis of gastric cancer cells in vitro in a time- and dose-dependent manner. Results: We demonstrate that OSU-03012 induces cell death through endoplasmic reticulum stress (ERS) mediated up-regulation of PTEN, sequentially followed by the suppression of Akt-STAT3 axis, the activation of the mitochondrial membrane protein Bim, mitochondrial damage and finally the release of the caspase family proteases. Conclusions: Our data provide evidences to support OSU-03012 as a potential therapeutic agent for gastric cancer, which may facilitate further preclinical development of anti-tumor drugs.
Growth differentiation factor 15 (GDF-15) inhibition to increase muscle mass and function in cancer cachexia.
Authors: Peloquin Matthew , LaCarubba Brianna , Joaqium Stephanie , Weber Gregory , Stansfield John , Bezy Olivier , Kim-Muller Ja Young , Breen Danna , Wu Zhidan , Zhang Bei Betty
Published: May 2020

e15633

Background: Almost half of cancer deaths are attributed to cancers most frequently associated with cachexia. Cachexia is a complex metabolic disease characterized by anorexia and unintentional weight loss. Skeletal muscle depletion has been recognized as a key feature of the disease, however muscle anabolic therapies have not been successful, suggesting that treatments that target multiple aspects of the disease will be most effective. Growth differentiation factor 15 (GDF-15) is a cytokine that induces anorexia and weight loss and is associated with cachexia in cancer patients. In preclinical cancer cachexia models, GDF-15 inhibition is sufficient to normalize food intake and body weight, including skeletal muscle mass. However, it remains to be determined whether the increased skeletal muscle mass also results in restoration of muscle function. Therefore, we examined the effect of GDF-15 inhibition on muscle mass and function in mouse models of cancer cachexia in comparison with myostatin inhibition, an established muscle anabolic pathway. Methods: Cachectic mouse tumor models were established with subcutaneous implantation of tumor cell lines reported to be GDF-15-dependent; mouse renal cell carcinoma (RENCA) and human ovarian cancer (TOV-21G) cell lines. Mice were treated with anti-GDF-15 (mAB2) or anti-myostatin (RK35) monoclonal antibodies and skeletal muscle function was assessed in vivo via maximum force, maximum rate of contraction and half relax time. In the RENCA tumor model, GDF-15 inhibition fully restored body weight and skeletal muscle mass whereas myostatin inhibition showed only a modest effect. Results: Consistent with the muscle mass improvement, GDF-15 inhibition dramatically increased functional muscle endpoints compared to the partial effect of myostatin inhibition. Interestingly, in the TOV-21G tumor model GDF-15 inhibition only partially restored body weight, however skeletal muscle mass and muscle function were completely normalized. Consistent with the functional assessment, GDF-15 inhibition in the RENCA tumor model decreased the expression of several catabolic genes (i.e. Trim63, Fbxo32, Myh7 and Myh2). The GDF-15 effect is likely to be secondary to the reversal of anorexia since wildtype mice pair-fed to Fc-GDF-15-treated mice demonstrated equivalent muscle mass loss. Conclusions: Taken together these data suggest that GDF-15 inhibition holds potential as an effective therapeutic approach to alleviate multiple aspects of cachexia.
Studies on the efficacy of pyrotinib in the treatment of HER-2 positive advanced solid tumors.
Authors: Fan Shaoshuang , Jiang Da , Lv Yalei , Cui Yanzhi , Kong Yan , Dong Qian , Huang Fang , Zhang Xue , Wang Long , Zhou Xinliang , Jin Hui , Li Ying , Hou Ran
Published: May 2020

e15639

Background: To explore the efficacy and safety of pyrotinib in the treatment of HER-2 positive advanced solid tumors patients. Methods: Patients with HER-2 positive advanced solid tumors in oncology department of our hospital from October 2018 to Janurary 2020 were collected. All the patients were given oral pyrotinib 400mg once a day in a 28-day cycle. The clinicopathological characteristics, treatment history, and curative effect were collected, and the adverse reactions related to the treatment were recorded. Results: 13 patients with HER-2 positive advanced solid tumors were enrolled, including 11 patients with metastatic breast cancer, 3 patients with metastatic colon cancer, 3 patients with gastric cancer. Among them, 10 patients were evaluated for efficacy and(or) side effect, of which 3 patients were excluded because they were not taken pyrotinib according to the medical order or they had no complete follow up data. The total mPFS was 5.63 months (95%CI: 2.533-5.467), partial remission (PR) were 3 cases(30%), stead diease(SD) were 6 cases(60%), progress diease was 1 case(10%). The overall response rate (ORR) and the disease control rate (DCR) were 23.1%, 69.2%, respectively. 2 patients received first-line treatment and 11 patients received second-or-further-line treatment. 11 cases of trastuzumab were changed to anti-HER-2 after treatment failure, of which 2 cases were treated with pirotinib after trastuzumab and lapatinib failed treatment. 12 cases with HER-2 overexpression and 1 case with HER-2 amplification. The incidence of pyrotinib side effects was 100%, which occurred in the first cycle of treatment and was common in grade 1 and 2. The common symptoms were diarrhea (100%), hand and foot skin reaction (38%), rash (8%), etc. Grade 3 to 4 adverse events occurred in 1 patient (8%) received pyrotinib plus capecitabine. 1 patient reduced pyrotinib dosage because of diarrhea. Nevertheless, diarrhea did not lead to discontinuation. Conclusions: The treatment of HER-2 positive advanced solid tumors with pyrotinib have good exact affect, and the toxicity could be controlled.
Effect of metallic nanoparticles on tumor growth: In vivo study.
Authors: Zlatnik Elena Yu. , Triandafilidi Elena I. , Bykadorova Oksana V. , Kit Oleg I. , Zhukova Galina V. , Goroshinskaya Irina A.
Published: May 2020

e15650

Background: The aim of the study was to assess the effect of metallic nanoparticles on growth of transplanted ascitic tumor sarcoma 37 in mice. Methods: Nanoparticles (NP) of transition metals were experimentally developed and kindly provided us by Prof. V.B. Borodulin. Ultradispersed metallic powders (NP Cu, NP Zn, NP Fe) 30-100 nm sized were dispersed by ultrasound in 0.85% NaCl before use and daily administrated intraperitoneally to tumor-bearing mice with ascitic sarcoma 37. Injections of NP 500 µl (10 µg/ml) were performed for 4 days, and 4 days after the completion of the course mice were sacrificed. The control group received 0.85% NaCl. Ascitic fluid volume was measured and living cells were counted. Results: In all the tumor-bearing mice the progression of ascites was noted: it was maximal in controls, less in animals having received NP Fe and NP Cu, minimal – in mice after injection of NP Zn. The volume of the latter was 0.78±0.31 ml in comparison with control data: 1.79±0.66 ml (p < 0.05); it was also less than in mice after administration of NP Cu (2.16±0.68 ml) and NP Fe (3.3±1.3 ml). Similar difference was seen in the amount of tumor cells in ascitic fluid: (1.67±0.5)х106/ml after the injection of NP Zn and (27.7±2.86)х106/мл in the control group. Effect of NP Cu and NP Fe was less pronounced than of NP Zn though obvious in spite of the noted tendency of the increase of the ascitic fluid volume. The most significant changes were observed when absolute amount of living tumor cells was counted per one mouse – it was minimal after NP Zn administration (0.636±0.2)х106/ml and maximal in the control group (23.98±10.5)х106/ml), i.e. only 2.6% of tumor cells had survived after NP Zn injection. Conclusions: Our results demonstrate that metallic NP were able to produce antitumor in vivo without any supplements like laser or hyperthermia: the effect was likely to depend upon the metal and was the highest in NP Zn compared to NP Cu and Fe.
Role of mutant KRAS as a biomarker in FL118-induced apoptosis, reactive oxygen species (ROS) production and inhibition of survivin, Mcl-1 and XIAP in human bladder cancer.
Authors: Santha Sreevidya , Aljahdali Ieman , Rasam Sailee Suryakant , Wang Xue , Ling Xiang , Liao Jianqun , Wang Jue , Fountzilas Christos , Li Qingyong , Qu Jun , Li Fengzhi
Published: May 2020

e15651

Background: Effective treatment of bladder cancer patients has not been realized over the past two decades due to heterogeneity with key oncogenic and tumor suppressor gene mutations, which is a major hurdle for effective treatment of the disease. Methods: Cancer cell growth/viability was determined using MTT assays; protein gene expression profiles were determined by both Western blots and proteomics technologies; PARP cleavage were determined by Western blots; genetic modulation of protein gene expression was realized by shRNA silencing or forced expression of the gene; reactive oxygen species (ROS) production was measured using a ROS assay kit; and human bladder xenograft tumor growth was determined using animal models. Results: Our study indicated that FL118, an innovative small molecule, exhibits differential anticancer efficacy in high-grade bladder cancer cell lines (HT1376, T24, UMUC-3). FL118 is highly effective at inhibiting the viability of T24 and UMUC-3 bladder cancer cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 with wild-type Ras exhibits insensitivity to FL118-mediated inhibition of cell viability. Consistently, FL118 strongly induced PARP cleavage (hallmark of apoptosis) and inhibited the expression of survivin, XIAP and/or Mcl-1 in both T24 and UMUC-3 cells but not in the HT1376 cells. Our studies further indicated that the constitutive AKT and ERK1/2 signaling does not play a major role in these FL118-mediated effects. Instead, mutant Kras appeared to be involved in FL118 efficacy and played a positive role in mediating FL118 effects. Silencing of mutant Kras via shRNA reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC-3 cells, suggesting mutant Kras is required for FL118 to exhibit high efficacy. FL118 increases ROS production in T24 and UMUC-3 cells but not in HT1376 cells. Silencing of mutant Kras with shRNA in UMUC-3 cells significantly reduced FL118-mediated ROS generation. Additionally, proteomics analyses of UMUC3 and HT1376 cell protein profiles after FL118 treatment support the obtained results described above. Consistent with these in vitro results, in vivo studies indicated that UMUC3 is highly sensitive and HT1376 is highly resistant to FL118 treatment. Conclusions: Our studies suggest that mutant Kras is a favorable biomarker for FL118 targeted treatment in human bladder cancer.
FGFR2 inhibition could suppress spermatogenesis.
Authors: Tsimafeyeu Ilya , Lapina Nataliya , Byakhov Mikhail , Dragun Nadezhda , Gavrilova Evgenia , Skorobogatova Anastasia , Stosman Kira , Melikhova Marina , Vakunenkova Olga , Kashuro Vadim , Rozhko Mikhail , Tjulandin Sergei
Published: May 2020

e15659

Background: The incidence of cancer among the people of reproductive age is constantly increasing. Although FGF2/FGFR2 expression in the male reproductive tract has been reported, there is no evidence of the impact of FGFRs inhibitors on sperm function. Therefore, the objective of this large study was to determine the effects of alofanib, selective FGFR2 allosteric extracellular inhibitor on the regulation of sperm physiology using the rat and rabbit models. Methods: Two-hundred forty Sprague-Dawley rats and 30 Chinchilla white rabbits received alofanib (0–40.5 and 0–21.6 mg/kg/day, respectively) intravenously on a consecutive daily dosing schedule for six months. Eighty rats and 8 rabbits were in the control group. The subchronic study evaluated high doses (300 mg/kg/day) of alofanib for 2 months in 15 male rats. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. Results: Animals were active. After injections of a dose equivalent to a human therapeutic dose during 6 months, most of the seminiferous tubules were empty, the elements of spermatogenesis were not classified, and altered primary spermatogonia and spermatocytes were distinguished in male rats. After injections of a five-fold dose, all seminiferous tubules were empty and expelled by a cylindrical epithelium. Very similar changes in sperm physiology were founded in rabbits. Most of the seminiferous tubules were blank, and some tubules contained eosinophilic amorphous masses. High doses of alofanib resulted in pronounced atrophy of the spermatogenic tubule epithelium. Multinucleated giant cells were observed in the lumen of a part of the tubules. There were no changes in untreated animals. Conclusions: FGFR2 inhibition led to the suppression of spermatogenesis. Male cancer patients should be informed of this potential adverse event before treatment with FGFR2 inhibitors.
Novel CTC test followed by iodine therapy for the terminal stage of cancer patients.
Authors: Shirakawa Taro
Published: May 2020

e15661

Background: 5 years of survival rate of stage IV cancer patients have kept poor for these 30 years. This is mainly due to inevitability of anti-cancer drugs for them because of multi-organ metastasis. We developed a novel CTC technique to identify CTCs responsible for metastasis, and provided a method to kill those dangerous cells by Iodine therapy. Methods: We did 314 CTC tests, and 53 patients received it more than twice (average prognosis of 4.5 months). Our CTC tests by flouring 4cc blood of the patients into a special device with > 50,000 pores of 8μ diameters, this device can only catch CTCs. We also stained with cytokeratin and vimentin anti-bodies (see table). Iodine water was made of 10,000 ppm of NaI with certain numbers of additional chemicals. This preclinical trial was accepted by our ethical committee. Results: We developed a novel CTC technique to catch 95% of CTCs and identified 3 types of CTCs (see table). Without any therapy, type 1 cells disappeared, while all patients with type 2 cells died within a couple of months, this may be due to EMT (epithelial mesenchymal transformation) on them. We tested certain numbers of ant-cancer drugs and found that no drugs can kill type 2 cells, only stable Iodine water provided by our clinic can kill type 2 cells perfectly within two months, and 51 out of 53, the terminal stage of patients can survive more than a year. Conclusions: Novel CTC test can identify 3 types of CTCs and type 2 cells can be responsible for the poor survival of terminal stage cancer patients because they are responsible for metastasis, and anti-cancer drugs cannot kill them. It has been well-known that Iodine induces PPARγ which can promote apoptosis of type 2 cells and inhibit EMT. Iodine may improve their poor prognosis.[Table: see text]
Preclinical evaluation of LX-086, a small molecule as a selective inhibitor of PI3K.
Authors: Dong Jiaqiang , Wang Tie-Lin , Huang Jingjie , Zhou Ji , Tan Ye , Yu Tao , Wu Chengde , Chen Shuhui
Published: May 2020

e15662

Background: PI3K/Akt signaling pathway plays a key role in a series of cellular functions related to cell growth, proliferation, survival and differentiation. PI3Kα is ubiquitously expressed, and associates with angiogenesis and glucose homeostasis. Gain of function mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common somatic alterations in solid tumors. The purpose of this study is to investigate the in vitro/ in vivo antitumor activity, and safety of LX-086, a small molecule of PI3Kα selective inhibitor, in preclinical models of solid cancer with PIK3CA mutation or amplification. Methods: Kinase inhibitory activity and selectivity of LX-086 were determined with PI3K kinase assays. Cellular pAktS473 inhibitory activity and selectivity were evaluated in BT-474, MDA-MB-468, RAW264.7 and Jeko-1 cell lines (cell lines PI3Kα/β/γ/δ are specifically highly expressed respectively). The antitumor activity of LX-086 was evaluated in vivo in PIK3CA amplified or mutant breast cancer BT-474, T47D and ovarian cancer SK-OV-3 cell-derived mouse xenograft (CDX) models. Results: LX-086 displayed potent kinase inhibitory activity for WT PI3Kα, PI3KαE545K, PI3KαH1047R with IC50 1.80 nM/1.13 nM/0.69 nM, respectively. LX-086 inhibited cell pAktS473 in BT-474 cells with IC50 35.4 nM. The selectivity of LX-086 in PI3Kα over PI3Kβ/δ/γ is similar with that of alpelisib, which had been approved by FDA in 2019. LX-086 showed antitumor efficacy in HER2+/HR+, PIK3CA amplified breast cancer BT-474 CDX model (TGI = 106% @40 mpk, QD), as well as in the HER2-/HR+, PIK3CA H1047R breast cancer T47D CDX model ( TGI = 84.7%@ 40 mpk, QD) and PIK3CA H1047R ovarian cancer SK-OV-3 CDX model ( TGI = 69.2%@ 40 mpk, QD). The 28-days toxicity study in dog also indicated that LX-086 had similar therapeutic index with alpelisib, with low risk of hyperglycemia. Conclusions: We have identified a novel potent and safe PI3Kα inhibitor LX-086. Preclinical studies show antitumor efficacy of LX-086 in PIK3CA mutant and amplified solid cancer models. LX-086 represents a promising clinical candidate for the treatment of solid cancers with PIK3CA mutation or amplification.
Pharmacodynamic effects in blood and tumor tissue of eftozanermin alfa, a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist.
Authors: Motwani Monica , Modi Dimple , Penugonda Sudhir , Zhang Chun , Palma Joann , Cunningham Alexis , Calvo Emiliano , de Jonge Maja J.A. , LoRusso Patricia
Published: May 2020

e15668

Background: Eftozanermin alfa (eftoza; formerly known as ABBV-621), a 2nd-generation tumor necrosis factor-related apoptosis-inducing ligand receptor agonist, is being evaluated in previously treated solid and hematologic malignancies (NCT03082209). In a dose-expansion cohort, patients (pts) with KRAS-mutant colorectal cancer (n = 24) and pancreatic cancer (n = 24) were evaluated at 3 dose levels with 12 mandatory paired biopsies per tumor type (pretreatment [Tx] and on-Tx collection). Following eftoza dosing, RNA and protein expression including posttranslational modifications were assessed in tumor biopsies to understand the target engagement and downstream pathway activation. Plasma was evaluated for changes in somatic mutant allele frequency and M30, M65 (circulating apoptotic markers). Methods: Biopsies were collected anytime during the screening period (pre-Tx) and 24±4 h following 2nd or 3rd infusion (on-Tx). Of the requested 4–6 fresh biopsy cores, 1–2 cores were collected as formalin fixed paraffin embedded (FFPE) and the rest were frozen tissue. FFPE tissue was analyzed by multiplex immunohistochemistry (IHC) and RNAseq; reverse phase protein array was used for frozen cores. Plasma was collected at cycle 1 predose and 2, 8, 24, 48, and 168 h postdose and analyzed for M30, M65 (by ELISA) and circulating tumor DNA (64-gene PlasmaSELECT assay). Results: Twenty-five pts consented to biopsies; paired biopsies were obtained from 16 pts at a 64% success rate: FFPE (n = 15) and frozen cores (n = 12). Tumor cells were detected in 11/15 (73%) FFPE and 4/12 (33%) frozen cores. Increase in M30, activated caspases, and cleaved PARP levels was observed in on-Tx biopsy samples compared with pre-Tx, thus serving as evidence for apoptosis induction in tumors following eftoza dosing. Changes in the tumor microenvironment were observed post-Tx by RNAseq and multiplex IHC (eg, CD68 level). Downregulation of prosurvival signaling pathways (eg, AKT/MEK) was also observed following eftoza dosing. Thirteen out of 16 pts showed transient increase in mutant allele fractions post eftoza Tx that correlated with increased plasma circulating tumor markers M30 and M65 at similar time points, suggesting activation of apoptosis pathway. Increase in M30, M65 levels also preceded increase in liver enzymes (ALT/AST) at 2, 48 hr post-Tx. Conclusions: Pharmacodynamic effect of eftoza was successfully demonstrated in blood and tumor tissue, including induction of apoptosis and modulation of PI3K and MEK signaling pathways. Clinical trial information: NCT03082209.
Actionable alterations (AA) in gastrointestinal (GI) cancers: Rate of detection and receipt of matched therapies (MT).
Authors: Greally Megan , Tuvy Yaelle , Millang Brittanie M , O'Reilly Eileen Mary , Yaeger Rona , Saltz Leonard B. , Ku Geoffrey Yuyat
Published: May 2020

e15677

Background: Next generation sequencing (NGS) is widely used in pts with advanced cancer to personalize care. Current NCCN guidelines endorse Her2, PD-L1 and MSI testing in esophagogastric cancer (EGC), RAS, BRAF, Her2 and MSI testing in colorectal cancer (CRC) and germline, somatic and MSI testing in pancreas cancer (PC). The proportion of GI cancer pts who receive MT based on NGS is unclear. Methods: We identified pts with advanced EGC (2016-18), PC (2017) and CRC (2016) who underwent NGS with MSK-IMPACT. We assessed the proportion of pts with ≥1 AA as defined by OncoKB (at the time of analysis, levels 1/2a were accepted practice and levels 2b/3/4 were investigational; Chakravaty, JCO PO 2017), those who received MT on trial or off label and 3 and 6 months (mos) progression-free survival (PFS). Results: We identified 260 EGC, 357 PC and 438 CRC pts. After excluding pts who had ongoing benefit from standard therapy (tx), were treated elsewhere or had no active stage IV disease, potential level 2/3/4 AAs occurred in 37% (n = 97) of EGC pts, 32.5% (n = 116) of PC pts and 26.7% (n = 117) of CRC pts (Table). 10, 1 and 17 pts with EGC, PC and CRC respectively were MSI. 1 pt in each subtype had an NTRK fusion (OncoKB level 1). In EGC, 6 pts (6.2% of those with AAs) received MT: 2 pts with MET amplification (a) and 1 each with BRCA2 mutation (m), TSC2m, ERBB2m and EGFRa. The pts with METa treated with crizotinib achieved 3 but not 6 mos PFS. In PC, 11 pts (9.5%) got MT: 10 pts for BRCAm and 1 for NTRK3 fusion. 9 pts with BRCAm treated with PARP inhibitors (i) achieved ≥3 mos PFS and 5 pts reached ≥6 mos PFS. The pt treated with NTRKi progressed rapidly. In CRC, 5 pts with ERBB2a and 9 pts with BRAFm received MT (12%). 3 pts and 2 pts treated with anti-Her2 tx achieved ≥3 and ≥6 mos PFS respectively. Of 6 pts treated with BRAF/MEKi plus irinotecan or anti-EGFR tx, all achieved ≥3 mos PFS; 3 reached ≥6 mos PFS. 3 pts received novel BRAF and ERK1/2i; none reached 3 mos PFS. Conclusions: NGS frequently identified OncoKB level 2 AAs. Few pts received MT, and of those, some achieved ≥6 mos PFS. Pts with CRC and PC received MT which subsequently became standard NCCN recommendations; therefore, a more current analysis may show increased MT use. Still, MT for level 3 and 4 alterations were rare, suggesting expectations of NGS must be managed appropriately. [Table: see text]
Hepatic arterial infusion (HAI) chemotherapy via the medtronic pump-assessing dose delivery, response rates and toxicity.
Authors: Connell Louise Catherine , Fiedler Laura , Dickinson Shannan , Ly Michele , Harrington Kate , Jarnagin William R. , Kingham T. Peter , Drebin Jeffery A. , Balachandran Vinod P. , Wei Alice C. , D'Angelica Michael Ian , Kemeny Nancy E.
Published: May 2020

e16007

Background: Due to the termination of the Codman pump, in order to administer hepatic arterial infusion (HAI) chemotherapy, the Medtronic pump has been used with the Codman catheter at MSKCC since 2018. Methods: Retrospective review of patients(pts) receiving HAI therapy via Medtronic pumps. Expected versus actual dose delivery of HAI FUDR, response rates and safety were reviewed. Results: Pts included; unresectable colorectal liver metastases (CRLM) (94 pts), resected CLRM (66 pts) and unresectable intrahepatic cholangiocarcinoma (ICC) (11 pts). Baseline characteristics of the 171 evaluable pts are shown in Table. In 120 pts with mCRC, 51.8% (n = 58) had 10 or more hepatic tumors and 23.2%( n = 26) had 50% or more liver involvement by metastases. 52 out of 171 pts (30.4%) had 100% of the expected FUDR doses by completion of the 3rdcycle. Another 49.7% (85/171) had greater than or equal to 50% of the expected FUDR dose. 96 pts had measurable disease (unresectable CLRM and ICC subgroups) evaluated by RECIST 1.1 with an MSK radiologist. The partial response for unresectable CRLM pts was 47% (41/87), and 28% (24/87) were stable. The partial response for ICC pts was 22% (2/9), and 33% (3/9) were stable. Conclusions: We evaluated 171 pts who were heavily pretreated and had extensive disease prior to pump placement. Partial response by RECIST 1.1 of 47% was evident in those pts with CRLM and 22% for pts with ICC. Dose delivery of HAI FUDR was compatible with that seen with the Codman pump and no increase in toxicity was noted. An updated analysis with additional evaluable pts will be presented at the meeting. [Table: see text]
Clinical implications of assumptions in cost-effectiveness analyses of systemic therapies for metastatic colorectal cancer.
Authors: Degeling Koen , Vu Martin , Koffijberg Hendrik , Wong Hui-Li , Koopman Miriam , Gibbs Peter , IJzerman Maarten J.
Published: May 2020

e16021

Background: Considerable variation is observed in model-based cost-effectiveness analyses of systemic therapies for metastatic colorectal cancer (mCRC). This review provides a comprehensive and detailed discussion of structural and methodological assumptions in such analyses, and how those might impact health and economic outcomes. Methods: Five databases (EMBASE, MEDLINE, Cochrane Library, Health Technology Assessment, and National Health Service Health Economic Evaluation Database) were searched for model-based health economic evaluations of systemic mCRC treatment. Study selection, appraisal using the Consolidated Health Economic Evaluation Reporting Standards checklist, and data extraction was performed by two reviewers independently. Data extraction included general study characteristics, economic methods and assumptions, model structures and modelling technique, evidence used, extrapolation methods, validation efforts, and analyses performed. Economic outcomes were indexed to 2019 US$. Results: The search yielded 1,418 publications of which 54 were included, representing 51 unique studies. Most studies focused on first-line treatment (n = 29, 57%), followed by third-line treatment (n = 13, 25%). Although most studies mentioned consideration of further treatments (n = 29, 57%), this was typically only done by means of a lumpsum treatment cost (n = 21). Studies used varied modelling techniques and model structures, and different control strategies were adopted by studies aiming to estimate the cost-effectiveness of the same treatment. Only 15 studies (29%) reported some sort of model validation. Health economic outcomes for specific strategies differed substantially between studies. For example, survival following first-line treatment with fluorouracil, leucovorin, and oxaliplatin ranged from 1.21 to 7.33 years, with treatment costs ranging from US$8,125 to US$126,606. Conclusions: Model-based cost-effectiveness analyses of systemic mCRC treatments have adopted varied modelling methods and structures, which has resulted in substantial different health economic outcome estimates between studies, for example in terms of overall survival and average treatment cost per patient. Models generally focus on first-line treatment without considering the use of downstream treatments, suggesting these studies likely present biased results. This may impact the uptake of new systemic therapies.
Bevacizumab plus S-1 and raltitrexed for refractory metastatic colorectal cancer.
Authors: Chen Ye , Liu Jiyan , Gou Hongfeng
Published: May 2020

e16024

Background: There are lack of effective drugs and regimens for refractory metastatic colorectal cancer (mCRC), especially in China. Dihydropyrimidine dehydrogenase (DPD) is the rate limiting enzyme of 5-FU catabolic pathway. Thymidylate synthase (TS) is the target of 5-FU anti-tumor mechanism. Several studies have shown the up-regulation of the two enzymes after the use of 5-FU in colorectal cancer, which may be closely related to the 5-FU resistance. The preliminary research of our center has shown the efficacy and safety of S-1 (containing a DPD inhibitor) plus raltitrexed (a TS inhibitor) in refractory mCRC. The aim of this study is to evaluate the efficacy and safety of bevacizumab plus S-1 and raltitrexed for patients with mCRC after failure to fluoropyrimidine, irinotecan and oxaliplatin. Methods: This study is a one-center, single-arm, prospective phase II trial, being carried out in the Cancer Center, West China Hospital, Sichuan University, China. The patients who have progressed after the treatment of fluoropyrimidine, irinotecanand oxaliplatin, have at least one measurable lesion according to RECIST 1.1 criteria were enrolled. Patients receive bevacizumab 7.5mg/kg and raltitrexed 3 mg/m2 on days 1 plus S-1 80, 100 or 120 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. Results: From Sep 2015 to Nov 2019, 44 patients were enrolled. By Feb 5, 2020, eleven patients were alive. Tumor response evaluation was available in 44 patients at the time of the analysis. There was no complete response, ORR was 15.9%(7/14) and disease control rate was 54.5%(24/44). mPFS and mOS were 110 days (95% confidence interval, 65.0-155.0) and 367 days (95% confidence interval, 310.4-423.6). The most common adverse events were bone marrow depression, dysfunction of digestive system abnormality of liver function and bleeding. Most of these adverse events were mild to moderate. Conclusions: Bevacizumab plus S-1 and raltitrexed further showed its moderate effect for refractory mCRC. Most of the adverse effects were mild to moderate, which could be well controlled. This combined regimen is worthy of further study as third or later line therapy in mCRC. Clinical trial information: ChiCTR1900020485 .
Efficacy of single-agent epidermal growth factor receptor inhibition in the second-line setting for metastatic colorectal cancer with a goal towards retreatment strategies.
Authors: Kratz Jeremy D. , LoConte Noelle K. , Lubner Sam Joseph , Mulkerin Daniel , Uboha Nataliya Volodymyrivna , Deming Dustin A.
Published: May 2020

e16035

Background: Advances in the understanding of colorectal cancer (CRC) biology, including clonal evolution are leading to novel treatment strategies. Epidermal growth factor receptor inhibition (EGFRi) with cetuximab or panitumumab has shown significant clinical utility in KRAS/NRAS/BRAF wildtype (wt) CRC. These inhibitors are most commonly used in the third-line treatment setting in the United States. Upon the development of resistance to EGFRi, withdrawal of the EGFR inhibitor can lead to decay of resistant clones allowing for EGFR inhibitor retreatment in additional lines of treatment. Earlier-line use of single agent EGFRi could allow more patients to utilize a retreatment strategy, however no large prospective clinical trials have assessed the clinical activity of second line EGFRi in the setting of molecular selection. Here, we assess the clinical outcomes of EGFRi monotherapy for advanced KRAS wt CRC after initial progression on a single line 5FU based chemotherapy. Methods: A retrospective chart review examined patients who received single agent EGFRi in KRAS wt CRC in the second line setting. Line of therapy was defined at time of metastatic disease or recurrence within 6 months of adjuvant therapy. Clinical outcomes of overall response rate (ORR) and progression free survival (PFS) were assessed per RECIST v1.1. Results: 20 cases were identified who received single agent EGFRi (panitumumab or cetuximab) as monotherapy in the second line setting. All pts received prior 5FU based chemotherapy. Reasons for using EGFR inhibitor monotherapy in this setting included to avoid toxicities from prior chemotherapy (largely immunosuppression and GI toxicities), bridge from recent operative management, or maintain functional performance status. Patients had median age of 62 [45, 89] and majority with ECOG PS 0-1 (78.5% of those reported). Best responses included complete response 7%, partial response 21%, stable disease 64% and progressive disease 7%, and a disease control rate of 93%. The 6 and 8 month PFS were 70% and 50%, respectively. PFS ranged from 1.5 to 17.3 months with median PFS 8.2 ± 3.6 months. Conclusions: This work demonstrates preliminary efficacy data to use single agent EGFRi in the second-line setting for KRASwt patients with CRC. Future investigations will aim to prospectively validate the benefit of this treatment strategy to facilitate EGFRi retreatment and improve patient survival.
LM02-trial perioperative treatment with panitumumab and FOLFIRI in patients with wild-type RAS, potentially resectable colorectal cancer liver metastases.
Authors: Piringer Gudrun , Gruenberger Thomas , Kuehrer Irene , Oefner Dietmar , Kaczirek Klaus , Laengle Friedrich , Viragos-Toth Istvan Levente , Amann Arno , Eisterer Wolfgang , Fuegger Reinhold , Andel Johannes , Pichler Angelika , Stift Judith , Soelkner Lidija , Gnant Michael , Thaler Josef
Published: May 2020

e16046

Background: Nearly half of patients with colorectal cancer develop liver metastases and only 20% are initially resectable. Surgical resection of liver metastases results in five-year survival rates of 24-48%. Perioperative FOLFOX therapy increases progression free survival. In advanced disease the addition of targeting therapies to chemotherapy results in an overall survival advantage. In this study the efficacy and safety of perioperative panitumumab and FOLFIRI therapy were investigated. Methods: Patients with previously untreated, wild-type RAS, potentially resectable colorectal cancer liver metastases were included. Chemotherapy consisted of irinotecan 180mg/m2 intravenously over 120 minutes and fluorouracil bolus 400mg/m2 intravenously, followed by a 46 h infusion of fluorouracil 2400mg/m2 repeated every 2 weeks. Panitumumab was given as an intravenous dose of 6mg/kg every 2 weeks. Preoperative 4 cycles and postoperative 8 cycles were administered. Primary objectives were the evaluation of efficacy and safety. Results: We enrolled 36 patients in 7 centers in Austria. ITT-analyses included 35 patients. There were 28 men and 7 women, the median age was 66 years. 91.4% completed the planned 4 cycles of preoperative therapy and 82.9% underwent liver resection. R0 resection rate was 82.7%. 20 patients started postoperative chemotherapy and 12 patients completed the planned 8 cycles. Objective response rate after preoperative therapy was 65.7% with one radiological complete remission and 22 partial remissions. In 20% and 5.7% of patients stable disease and progressive disease were documented, respectively. Three patients discontinued preoperative treatment due to adverse events without response evaluation. The most common grade 3 adverse events were diarrhea (n = 4), rash (n = 3) and leukopenia (n = 3) during preoperative therapy. One patient died due to sepsis and one had a pulmonary embolism grade 4. After surgery two patients died due to hepatic failure and one patient had a suture related complication grade 3. Most common grade 3/4 adverse events during postoperative therapy were rash (n = 2), stroke (n = 1) and intestinal obstruction (n = 1). Conclusions: Panitumumab in combination with FOLFIRI as preoperative therapy for operable colorectal liver metastases in RAS wild-type patients results in a radiological objective response rate in 65.7% of patients with a manageable grade 3 diarrhea rate of 14.3%. Progression-free survival and overall survival are still monitored. Clinical trial information: 2012_000265-20 .