bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT019: ASN003, a novel highly selective BRAF and PI3K dual inhibitor: Phase I PK/PD results in patients with advanced solid tumors
Authors: Rasco Drew , Lakhani Nehal , Sullivan Ryan , Mita Monica , Shah Jaimini , Usansky Helen , Reddy Sanjeeva , Rao Niranjan S. , Toker Sarper , Denis Louis , Flaherty Keith , Tolcher Anthony 
Published: August 2018

Abstract
Background RAS-RAF-MEK and PI3K-AKT-mTOR are two major pathways involved in tumor cell signaling and growth. Components of these pathways are frequently mutated in a broad range of tumors. ASN003 is a highly selective and potent (low nM IC50) inhibitor of BRAF and PI3K-α and -δ. ASN003 shows strong antitumor activity in tumor models harboring BRAF and PIK3CA mutations, and also in patient-derived xenograft (PDX) models that are resistant to selective BRAF and MEK inhibitors.
Patients and Methods: Oral once-daily ASN003 is being evaluated for safety/tolerability and preliminary efficacy in eligible patients with advanced solid tumors using an accelerated dose titration design (Part A) and enrolling cohorts of patients diagnosed with melanoma, CRC, NSCLC and other solid tumors with a BRAF, PIK3CA mutations at MTD (Part B). Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on tumor tissue biomarkers such as pERK and pS6 are being investigated in both parts of the study.
Results: Patient accrual in Part A is ongoing. As of January 2018, fifteen eligible patients were enrolled in dose levels ranging from 10 - 400 mg QD and 400 mg BID. ASN003 has been well tolerated. Treatment-related adverse events (TRAEs) were mostly mild (G1) to moderate (G2). TRAEs include, rash (G3), hypersensitivity (G3) (n=1), diarrhea (G2) (n=1), hyperglycemia (G2) (n=1), rash maculo-papular (G2) (n=1), vomiting (G1) (n=3), nausea (G1) (n=2), hyperglycemia (G1) (n=2), and dry mouth/lips/skin, transient blurred vision, rash acneiform, ALT increase, cognitive disturbance and hyperkalemia. The PK profile showed dose-dependent increase in systemic exposure at steady state (Cmax up to 5,990 ng/mL, AUC0-T up to 110,000 ng.h/mL) and a half-life of 14-25 hours in general. Early evidence of biomarker changes in repeat biopsies, and clinical disease control have been observed.
Conclusions: ASN003 is a novel small molecule, with uniquely selective and potent inhibition of BRAF, PI3K-α and -δ kinases. To date, ASN003 was well tolerated at doses up to 400 mg QD/BID and achieved good systemic exposure. Updated and detailed clinical safety/efficacy and PK/PD results will be presented.
Citation Format: Drew Rasco, Nehal Lakhani, Ryan Sullivan, Monica Mita, Jaimini Shah, Helen Usansky, Sanjeeva Reddy, Niranjan S. Rao, Sarper Toker, Louis Denis, Keith Flaherty, Anthony Tolcher. ASN003, a novel highly selective BRAF and PI3K dual inhibitor: Phase I PK/PD results in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT019.
Abstract CT056: The first-in-human clinical trial of MG7-CART for metastasis colon cancer
Authors: Yuan Jijun 
Published: August 2018

Abstract
MG7 antigen, a highly glycosylated CEACAM5 molecule, is specifically expressed in human gastrointestinal cancers. An MG7-CART therapy has been developed and showed great efficacy in gastric cancer PDX model. Here we present the first-in-human clinical trial results of MG7-CART therapy for metastasis colon cancer treatment.
Distal metastasis was observed in pelvic cavity, peritoneal, spleen, liver and uterus after the patient received 6 rounds of bevacizumab plus EXLOX treatments. Intratumoral injections of MG7-CART (1-1.2x107/site) were given to the patient sequentially in peritoneal, spleen and uterus metastasis and two rounds of intravenous injections of MG7-CART (1x107 to 1.5x108) were given at the same time.
Over 80% tumor necrosis could be observed in peritoneal and liver metastasis 40 days after injection and MG7-CART cell expansion could also be detected by PCR. During the treatment, the patient experienced transient body temperature increase and cytokine release.
The first-in-human clinical trial result showed that MG7-CART therapy is efficacious and safe with no observed adverse effects.
Citation Format: Jijun Yuan. The first-in-human clinical trial of MG7-CART for metastasis colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT056.
Abstract CT067: A phase Ib study of Toca 511, a retroviral replicating vector, followed by Toca FC in patients with advanced cancer
Authors: Merchan Jaime , Rodon Jordi , Falchook Gerald , Venkat Shree , Ostertag Derek , Tejera Dalissa , Kheoh Thian , Jolly Douglas J. , Gruber Harry E. , Shorr Jolene S. 
Published: August 2018

Abstract
Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic retroviral replicating vector (RRV) that selectively infects cancer cells. Toca 511 spreads through tumors, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug, Toca FC (investigational, extended-release 5-FC), into 5-FU. Based on preclinical studies, 5-FU kills infected dividing cancer cells and diffuses and kills surrounding cancer cells, myeloid derived suppressor cells, and tumor associated macrophages, thus reestablishing tumor immunity. In a previous Phase 1 study, intravenous (IV) injection of Toca 511 successfully delivered and expressed CD protein to high grade glioma tumors. In animal models of metastatic colorectal cancer, IV Toca 511 infected metastatic sites, and subsequent 5-FC treatment resulted in decreased tumor size and improved survival. Toca 6 is a Phase 1b, multicenter, open-label study in patients with advanced solid tumors or lymphoma (NCT02576665) designed to investigate changes in immune activity after treatment with Toca 511 & Toca FC. Vector deposition and transgene expression in tumor tissue following IV delivery of Toca 511 also is followed. Toca 511 is injected IV daily for 3 days, with subsequent injection either intratumorally after biopsy or, in the brain tumor setting, into resection cavity walls following resection. Oral Toca FC is started approximately 4 weeks later and repeated every 4-6 weeks. A total of 30 patients are planned to be enrolled. In patients treated to date, viral RNA, DNA, and CD protein expression after IV Toca 511 delivery have been detected in liver metastases from colorectal cancer and mesenteric lymph node metastases from pancreas cancer, demonstrating IV delivery of virus to and transgene expression in tumor. Preliminary data indicate treatment has been generally well tolerated to date, with few related adverse events. Data on changes from baseline in immune activity in tumor (infiltrating T-cell subpopulations, B cells, monocytes) and peripheral blood (effector, memory, Treg, and myeloid lineage cells), viral and CD protein expression in tumor, and safety will be presented.
Citation Format: Jaime Merchan, Jordi Rodon, Gerald Falchook, Shree Venkat, Derek Ostertag, Dalissa Tejera, Thian Kheoh, Douglas J. Jolly, Harry E. Gruber, Jolene S. Shorr. A phase Ib study of Toca 511, a retroviral replicating vector, followed by Toca FC in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT067.
Abstract LB-018: ARQ 531, a novel and reversible inhibitor of Bruton's tyrosine kinase, displays favorable oral bioavailability and exposure in patients with B-cell malignancies
Authors: Hall Terence , Yu Yi , Eathiraj Sudharshan , Stephens Deborah , Flinn Ian , Woyach Jennifer , Schwartz Brian , Savage Ronald E. 
Published: August 2018

Abstract
Background: ARQ 531 is a novel, ATP competitive reversible inhibitor Bruton's tyrosine kinase (BTK). BTK is a key regulator of the B cell receptor (BCR) signaling pathway that mediates signaling from the cell surface to the cytoplasm and into the nucleus. ARQ 531 is not metabolized by any of the major drug metabolizing CYP450 enzymes. Here we report pharmacokinetic profile of ARQ 531 in a phase I study evaluating safety, pharmacokinetics and pharmacodynamics activity and clinical activity of ARQ 531 in selected subjects with relapsed/refractory B-cell malignancies. Preclinical studies in rats, dogs and monkeys are also described.
Methods: Oral and intravenous single dose pharmacokinetic studies of ARQ 531 were conducted in rats, dogs, and monkeys to determine oral bioavailability and drug exposure. In a standard ‘3+3' dose-escalation study design, ARQ 531 was given orally once per day beginning at 5 mg/dose and escalating for 4 weeks [NCT03162536]. Plasma samples were collected to determine ARQ 531 concentrations and whole blood / PBMCx to quantify pBTK inhibition. Plasma samples from each species were analyzed by liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS).
Results: Consistent with preclinical studies, patients enrolled in the phase I study showed favorable exposures, the steady state peak to trough ratio was generally 3:1 or lower. ARQ 531 had an elimination half-life at steady state of ~24 hr and Cmax occurred 2 to 3 hours after dosing. Pharmacodynamic changes included suppression of BTK phosphorylation. No drug related AEs or DLTs have been observed thus far in the study.
Conclusions: ARQ 531 demonstrates a favorable PK profile in humans supporting once daily dosing. Sufficient plasma levels are attained and high levels of pBTK inhibition in peripheral blood can be achieved following oral dosing. Additional dose and schedule evaluations continue, and updated clinical and biomarker results will be presented.
Citation Format: Terence Hall, Yi Yu, Sudharshan Eathiraj, Deborah Stephens, Ian Flinn, Jennifer Woyach, Brian Schwartz, Ronald E. Savage. ARQ 531, a novel and reversible inhibitor of Bruton's tyrosine kinase, displays favorable oral bioavailability and exposure in patients with B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-018.
Abstract LB-045: Iron depletion suppress the stemness markers and functions of cancer stem cells
Authors: Ohara Toshiaki , Katsura Yuki , Noma Kazuhiro , Narusaka Toru , Kato Takuya , Sato Hiroaki , Komoto Satoshi , Tomono Yasuko , Ninomiya Takayuki , Tazawa Hiroshi , Kagawa Shunsuke , Shirakawa Yasuhiro , Fujiwara Toshiyoshi 
Published: August 2018

Abstract
Background: Cancer stem cells (CSCs) have been proposed to be responsible for tumor initiating, drug resistance, metastasis, and recurrence. Although CSCs are considered to be important targets therapeutically, clinically effective CSC targeting strategies have not yet been established. Iron plays an important role in critical cellular processes, such as energy production and DNA synthesis. Although adequate iron levels are essential for human health, iron overload is known to cause some types of cancer. CSCs are considered to be involved in the tumor regardless of early stage. Thus we have focused on the relationship between iron and CSCs. We previously reported that the expression of stemness markers was suppressed by iron chelator in miPS and miPS inducible CSC model cells (miPS-LLCcm). Here, we hypothesized that the expression of stemness markers and function were also suppressed by iron chelator in high malignant cancer cells with stemness potential.
Method: We used 4 stemness markers expressing cancer cell lines (HSC-2: Oral squamous cancer, TE-4 and OE33: Esophageal cancer, and NT-2: Embryonal cell carcinoma). Deferasirox (DFX), an oral iron chelator, was used. The stemness markers expression including Nanog, Sox2, Oct3/4, Klf-4 and c-Myc was examined by western blot analysis. Self-renewal ability was examined by sphere formation assay. Anti-proliferative effect of DFX was assessed combined with CDDP using HSC-2 cells.
Result: DFX suppressed the expression of stemness markers and sphere formation ability in 4 cancer cell lines. In contrast, CDDP could not suppressed them. In HSC-2 cells, combination therapy with CDDP and DFX synergistically suppressed the proliferation with suppression of stemness markers.
Conclusion: Our results indicated that iron depletion generally suppressed the stemness markers and functions of high malignant cells same as miPS and miPS-LLCcm. Thus iron depletion can be a novel therapy for CSCs via suppression of CSCs function.
Citation Format: Toshiaki Ohara, Yuki Katsura, Kazuhiro Noma, Toru Narusaka, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Yasuko Tomono, Takayuki Ninomiya, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Iron depletion suppress the stemness markers and functions of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-045.
Abstract LB-106: Allorepertoire-derived HLA class I/peptide-specific T cell receptor transgenic CD4+ T cells mediate antitumor responses in Ewing sarcoma mimicking allo-rejection
Authors: Schober Sebastian J. , Thiede Melanie , Schirmer David , Wohlleber Dirk , Richter Guenther , Busch Dirk H. , Thiel Uwe , Burdach Stefan E. 
Published: August 2018

Abstract
Introduction: Innovative therapies are urgently warranted to cure patients with advanced Ewing sarcoma (ES). Specific cellular-based approaches for immunotherapy of solid cancers show promising results in first clinical trials. Mostly, CD8+ effector T cells are genetically modified to recognize and kill tumor cells. In organ transplantation, alloreactive CD4+ T helper 1 cells have shown to be an underestimated key player in allo-rejection.
In previous works we observed massive CD4+ cell tissue-infiltration in tumor-free Rag2-/-c-/- mice after adoptive transfer of ES-specific CD8+ T cells combined with peripheral mononuclear cells in tumor bearing mice, suggesting an important role of CD4+ cells in disease control. In this study we transduce CD4+ T cells from healthy donors with an HLA class I allorepertoire-derived TCR specific for the ES-associated antigen STEAP1130 for which in vivo ES control by adoptively transferring CD8+ cells with the same transgene was demonstrated in previous works.
Methods: STEAP1/HLA-A*02:01 specific TCR transgenic CD4+ T cells were generated and characterized by flow cytometry, interferon-, granzyme-B release and xCelligence assays to study direct cytotoxicity and tumor growth inhibition, in comparison to STEAP1/HLA-A*02:01 specific TCR transgenic CD8+ T cells. In vivo functionality was validated in Rag2-/-c-/- mice.
Results: STEAP1/HLA-A*02:01 specific TCR CD4+ transduced T cells exhibit high peptide specificity. In vitro, CD4+ TCR transgenic T cells show similar tumor growth inhibition compared to CD8+ cells with the same transgene. Furthermore, in vivo data suggest a synergistic anti-ES effect of CD4+ and CD8+ cells transduced with the same STEAP1/HLA-A*02:01 specific TCR.
Conclusion: STEAP1/HLA-A*02:01 TCR transgenic CD4+ T cells exhibit direct cytotoxicity and execute synergistic helper functions. Combination of adoptively transferred TCR transgenic CD4+ and CD8+ T cells may result in better tumor control compared to transfer of respective TCR transgenic CD4+ or CD8+ T cells alone.
* U.T. and S.E.G.B. share senior authorship
Citation Format: Sebastian J. Schober, Melanie Thiede, David Schirmer, Dirk Wohlleber, Guenther Richter, Dirk H. Busch, Uwe Thiel, Stefan E. Burdach. Allorepertoire-derived HLA class I/peptide-specific T cell receptor transgenic CD4+ T cells mediate antitumor responses in Ewing sarcoma mimicking allo-rejection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-106.
Abstract LB-322: Casein kinase 2 is a major regulator of medulloblastoma growth
Authors: Nitta Ryan , Bolin Sara Matilda , Nwagbo Ginikachi , Purzner Teresa , Kahn Suzana , Cho Yoon-Jae , Li Gordon 
Published: August 2018

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for about 20% of all cases. While surgery, craniospinal irradiation, and chemotherapy have resulted in a cure rate of 70%, the surviving patients are afflicted with neurocognitive impairment, endocrine dysfunction, and a severe decrease in quality of life. Consequently, better and more effective treatments are needed to treat these young patients. Casein kinase 2 (CK2) is an intriguing therapeutic target for MB because it is dysregulated in all the MB molecular subgroups and patients with high CK2 expression have a significantly worse prognosis. To elucidate the role of CK2 in MB we transduced multiple MB cell lines with CK2 isoforms. We discovered that a CK2 isoform, CK2a, increased tumorigenesis in both the Sonic Hedgehog and Group 3 MB subgroups, while knocking down expression ameliorated MB growth. Through these transduced cell lines we also determined that CK2 can regulate MB tumorigenesis through b-catenin and potentially GLI1. Moreover, mice orthotopically injected with MB cells over-expressing CK2a or CK2b displayed a reduced survival compared to control. We extended our analysis to a CK2 inhibitor, CX-4945, which is currently undergoing phase I/II clinical trials for toxicity and safety. Treatment with CX-4945 reduced MB cell growth and also reduced expression of MGMT, a well-known regulator of temozolomide (TMZ) efficacy. Our findings were corroborated when we screened 4,000 FDA approved compounds to identify molecules that work synergistically with CX-4945. TMZ was one of the major compounds that were identified in the screen, suggesting that CX-4945 treatment can sensitize MB cells to TMZ by dysregulating MGMT. Combinatorial treatment with CX-4945 and TMZ had a synergistic effect on reducing MB tumor growth. Together, our findings suggest that CK2 is a novel therapeutic target for MB and that combining CX-4945 and TMZ can lead to a promising new MB therapy.
Citation Format: Ryan Nitta, Sara Matilda Bolin, Ginikachi Nwagbo, Teresa Purzner, Suzana Kahn, Yoon-Jae Cho, Gordon Li. Casein kinase 2 is a major regulator of medulloblastoma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-322.
Abstract LB-358: Abnormal O-glycosylation promotes prostate cancer stemness and mediates metastatic niche
Authors: Tsai Chin-Hsien , Tzeng Sheue-Fen 
Published: August 2018

Abstract
Oncofetal Galβ1-3GalNAc O-glycan, T antigen, is increased in about 60% carcinomas of breast, colon, stomach, and prostate. Notably, coexpression of T antigen with CD44 or CD133, markers of cancer stem cells, has been identified in lung, breast, and liver cancers. Using spontaneous metastasis model of 22Rv1 cells, we derived high metastatic 22Rv1-M4 cells and found altered O-glycosylation in the 22Rv1-M4 cells and also 22Rv1-M4-derived host microenvironment compared to parental cells. Our study indicated that high expressions of T antigen synthase C1GALT1 are associated with metastatic PCa and poor survival, probably contributed by the interaction of galectin-4 and glycan. Galectin-4 engaged with MYC-dependent C1GALT1 mediated O-glycan and resulted in RTK phosphorylation; activation of RTKs enhanced not only androgen-independent growth but also metastatic colonization which mediated by ERK-AP1-mediated SOX9 expression. Downregulation of SOX9 significantly inhibited the tumorsphere formation and in vivo metastasis. Moreover, coexpression of SOX9 and MYC in immortalized prostate epithelial cells RWPE1 generates the heterogeneous population presenting both epithelial type and cancer-like cells in mouse renal capsule. On the other hand, analyses of lung tissues from mice bearing tumor of 22Rv1-M4 cells relative to that bearing tumor of 22Rv1 parental cells exhibit the upregulated O-glycosylation enzymes, which associated with increased plant Jacalin lectin staining, CD45+ cells infiltration, and endothelial permeability indicated by dextran leakage. Tail-vein injection of 22Rv1-M4 cells exhibits aggressive systemic metastasis in a mouse conditioned by subcutaneous 22Rv1-M4 tumor compared to that in a mouse conditioned by subcutaneous 22Rv1 tumor These data suggest high metastatic prostate cancer cells adapt the lung microenvironment for seeding and colonization of cancer cells.
Citation Format: Chin-Hsien Tsai, Sheue-Fen Tzeng. Abnormal O-glycosylation promotes prostate cancer stemness and mediates metastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-358.
Abstract SY20-02: Inhibitor combinations targeting KRAS effector signaling in KRAS-mutant pancreatic cancer
Authors: Cox Adrienne D. , Goodwin Craig M. , Bryant Kirsten L. , Dagliyan Irem , George Samuel D. , Lucas Kelly E. , Gautam Prson , Wennerberg Krister , Der Channing J. 
Published: August 2018

Abstract
KRAS mutations are found in 95% of pancreatic ductal adenocarcinoma (PDAC), where they are key cancer drivers. Effective anti-KRAS therapeutics are thus anticipated to make a significant improvement in PDAC treatment. Despite the promise of inhibiting KRAS effector signaling, such inhibitors have not demonstrated significant activity as monotherapy, and there are concerns regarding potential normal tissue toxicity. Inhibitor combinations may overcome limitations of both efficacy and toxicity. We performed a 525-drug chemical biology screen to identify combinations that enhanced the cytotoxic activity of inhibitors of the RAF-MEK-ERK and the PI3K-AKT-mTOR effector pathways. Many such combinations were identified for RAF effector pathway inhibitors, while few were identified for PI3K pathway inhibitors. Generally, the same classes of inhibitors were identified for inhibitors of the RAF, MEK, and ERK nodes of the MAP kinase (MAPK) cascade. We found that inhibitors of the PI3K-AKT-mTOR pathway, microtubules, HDAC, and HSP90 each synergistically enhanced the cytotoxicity of RAF, MEK, and ERK inhibitors, in both conventional and PDX-derived PDAC cell lines. Mechanistically, we found that a shared basis for this synergy was enhanced loss of MYC protein, a key ERK substrate. Our studies identify promising combinations of KRAS effector inhibitors for PDAC treatment.
Citation Format: Adrienne D. Cox, Craig M. Goodwin, Kirsten L. Bryant, Irem Dagliyan, Samuel D. George, Kelly E. Lucas, Prson Gautam, Krister Wennerberg, Channing J. Der. Inhibitor combinations targeting KRAS effector signaling in KRAS-mutant pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY20-02.