bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B131: CD73 as a new target for glioblastoma therapy
Authors: Teixeira Fernanda Cardoso , Azambuja Juliana H , Teixeira Helder F , BRAGANHOL ELIZANDRA 
Published: March 2020

Abstract
Glioblastoma (GB) is the most common malignant brain tumor and is characterized by high invasiveness, poor prognosis, and limited therapeutic options. Studies silencing the gene expression using interference RNA tool (siRNA) have been proposed as new alternative for cancer therapy. Here, we evaluated the potential of CD73 as a new therapeutic target, because it is overexpressed in solid tumors and emerges as a promising target to control GB progression. A cationic nanoemulsion (NE) as siRNA-CD73 delivery system was developed and its effect on glioma growth was determined. The nanostructured system was effective to complex the oligonucleotides for delivering on target cells. In addition, we observed that the NE-siRNA-CD73 complex was effective to reduce CD73 protein levels and AMPase activity which was further related to decreased in vitro C6 glioma cell viability. In addition, blockade of CD73 by NE-siRNA CD73 delayed in vivo tumor growth in a preclinical glioblastoma model by inducing apoptosis. Meanwhile, significantly reduced the population of lymphocytes, particularly Tregs, which could be associated to the antiglioma effect induced by the treatment. The data indicate the potential of siRNA-CD73 loaded cationic nanoemulsion as a therapeutic alternative to glioma treatment.
Citation Format: Fernanda Cardoso Teixeira, Juliana H Azambuja, Helder F Teixeira, ELIZANDRA BRAGANHOL. CD73 as a new target for glioblastoma therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B131. doi:10.1158/1535-7163.TARG-19-B131
Abstract B132: Inhibition of Haspin kinase to promote cell-intrinsic and extrinsic anticancer therapy
Authors: Melms Johannes C. , Vallabhaneni Sreeram , Mills Caitlin E. , Wucherpfennig Kai , Sorger Peter K. , Izar Benjamin 
Published: March 2020

Abstract
Oncogene-targeted therapies are initially effective in most patients with BRAF-mutated melanoma. However, patients frequently develop resistance during therapy. At the time of therapy resistance, they are also less likely to respond to immune checkpoint inhibitors (ICI) with response rates ranging from 0-12%, compared to 40-60% when used in the first line. This may be in part be due to rapid tumor growth that outpaces pharmacodynamics of ICI. New drugs that directly control tumor growth and effectively enhance ICI activity are therefore needed. We report that the small molecule CX-6258 has potent activity against both RAF/MEK inhibitor (RMS) and resistant (RMR) BRAF-mutant melanoma cell lines. CX-6258 is annotated as a pan-PIM kinase inhibitor, with an EC50 corrected for growth rate (GR50) of ~200 nM; in contrast, other PIM inhibitors had no in vitro activity, suggesting that PIMs may not be the true target in melanoma - we therefore sought to systematically study the targets of this compound. Using an unbiased kinase profiling approach, we identified Haspin Kinase (HASPIN) as the key target of CX-6258 with an IC50~10nM. Haspin kinase (Haspin) is a poorly understood mitotic kinase, whose only well-defined function is phosphorylation of Histon H3 at Thr3 (pH3T3). Treatment with CX-6258 resulted in reduced proliferation, reduced phosphorylation of pH3T3, frequent formation of micronuclei (MN), recruitment of cGAS and activation of the cGAS-STING-pathway. By using CRISPR/CAS9 knock outs of PIM kinase we show that these targets are not required for CX-6258 function. Furthermore, siRNA mediated knock-down of HASPIN phenocopied CX-6258. In murine models, CX-6258 induces a potent cGAS dependent type-I-interferon response in tumor cells, increases IFNγ-producing CD8+ T-cells, reduces Tregs, and enhances responses to ICIs in vivo. HASPIN is more strongly expressed in malignant compared to healthy tissue and its inhibition by CX-6258 has minimal toxicity in ex vivo expanded human tumor-infiltrating-lymphocytes (TILs) and in vitro differentiated human neurons, suggesting a potential therapeutic index for anti-cancer therapy. CX-6258 also shows activity in several Ewing sarcoma and multiple myeloma cell lines with. In summary, HASPIN inhibition may overcome drug resistance in melanoma, synergize with ICIs and target a vulnerability in different cancer lineages.
Citation Format: Johannes C. Melms, Sreeram Vallabhaneni, Caitlin E. Mills, Kai Wucherpfennig, Peter K. Sorger, Benjamin Izar. Inhibition of Haspin kinase to promote cell-intrinsic and extrinsic anticancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B132. doi:10.1158/1535-7163.TARG-19-B132
Abstract B144: Lack of immunotherapy efficacy in a syngeneic bone metastasis model of triple-negative breast cancer
Authors: Kähkönen Tiina E , Suominen Mari I , Mäki-Jouppila Jenni HE , Halleen Jussi M , Bernoulli Jenni 
Published: March 2020

Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive cancer with treatment options limited to standard-of-care chemotherapy. TNBC patients develop metastases in high incidence, and almost all patients have bone metastases at end-stage disease. Bone metastases are mainly osteolytic, causing severe bone loss that can be prevented by bone-targeted agents. Currently, there is no efficient cure for bone metastases. Activation of the patient’s own immune system by immunotherapies is widely studied in various cancers, but their efficacy on bone metastases is not well established. In this study, we aimed to evaluate the efficacy of immunotherapies in comparison to standard-of-care compounds in a preclinical TNBC bone metastasis model. Materials and methods: Mouse 4T1-GFP TNBC cells were inoculated intracardially to immunocompetent female Balb/c mice to model bone metastasis. Treatment of single agents of chemotherapy (cyclophosphamide, 100 mg/kg), bone-targeting agent (zoledronic acid, 0.1 mg/kg), and immunotherapies programmed cell death 1 antibody (mouse anti-PD-1, 10 mg/kg) and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor (epacadostat, 100 mg/kg), and the combination of anti-PD-1 and epacadostat were started on the day following the cancer cell inoculations. The study was terminated 12-13 days after the inoculations. Tumor burden was evaluated by GFP imaging and tumor-induced bone loss by X-ray imaging at sacrifice. Tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemical stainings of CD3+, CD4+ and CD8+ T cells. Results: Cyclophosphamide decreased skeletal tumor burden and the area of tumor-induced osteolytic bone lesions. Zoledronic acid decreased the area of osteolytic lesions but had no effect on skeletal tumor burden. Anti-PD-1, epacadostat and their combination had no effect on skeletal tumor burden or in the development of osteolytic lesions. Low number or no TILs were observed in the tumors growing in bone obtained from vehicle-treated mice. Conclusions: Immunotherapies did not prevent tumor growth in bone or tumor-induced bone changes in the syngeneic TNBC model. This is probably caused by the low number of TILs in the tumors growing in bone. Further studies are needed to evaluate the effects of treatment combinations and to increase the responsiveness to immunotherapies especially in bone metastases.
Citation Format: Tiina E Kähkönen, Mari I Suominen, Jenni HE Mäki-Jouppila, Jussi M Halleen, Jenni Bernoulli. Lack of immunotherapy efficacy in a syngeneic bone metastasis model of triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B144. doi:10.1158/1535-7163.TARG-19-B144
Abstract C013: HI-B9 suppresses colorectal cancer by inhibiting Wnt/β-catenin pathway
Authors: Shin Seung Ho , Reddy Kanamata , Dong Zigang 
Published: March 2020

Abstract
Deregulated Wnt/β-catenin pathway plays an important role in colorectal cancer. β-Catenin interacts with transcription factor 7-like 2 (TCF7L2 or TCF4) to express oncogenes including c-myc, axin2 and cyclin D1. Here we describe a small molecule, referred to as HI-B9, which inhibits the growth of colorectal cancer cell lines. HI-B9 suppressed tryptophan fluorescence of β-catenin that contains TCF4-binding residues. In silico docking of HI-B9 on β-catenin showed a binding mode that blocks Lys 312 residue which is critical for the interaction between β-catenin and its interactors. A binding assay showed that the binding affinity of HI-B9 against β-catenin G307A/K312E mutant was significantly reduced compared to that against wildtype. HI-B9 inhibited β-catenin/TCF4 luciferase activity in a dose-dependent manner. Anchorage-independent growth of HCT116 and HT29 colorectal cancer cells were suppressed by the small molecule. mRNA expression levels of Wnt target genes were reduced by HI-B9 treatment. HI-B9 did not affect the translocation of β-catenin toward the nucleus. The therapeutic effects of HI-B9 was due to the disruption of β-catenin/TCF4 complex formation ex vivo. Our findings demonstrate the therapeutic potential of HI-B9 against colorectal cancer with aberrant Wnt/β-Catenin signaling pathway.
Citation Format: Seung Ho Shin, Kanamata Reddy, Zigang Dong. HI-B9 suppresses colorectal cancer by inhibiting Wnt/β-catenin pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C013. doi:10.1158/1535-7163.TARG-19-C013
Abstract C016: Oxidative phosphorylation is a metabolic vulnerability in chemotherapy resistant triple negative breast cancer
Authors: Evans Kurt , Moulder Stacy , Yuca Erkan , Scott Stephen , Arango Natalia Paez , Shariati Maryam , Vellano Christopher P , Saridogan Turcin , Zheng Xiaofeng , Gonzalez-Angulo Ana Maria , Zhao Ming , Su Xiaoping , Tapia Coya , Chen Ken , Akcakanat Argun , Perou Charles M , Lim Bora , Tripathy Debu , Yap Timothy A , Francesco Maria E Di , Draetta Giulio , Jones Philip , Marszalek Joe , Meric-Bernstam Funda 
Published: March 2020

Abstract
There is a pressing need to identify improved therapies for triple negative breast cancers (TNBC) resistant to standard chemotherapy. To identify potential molecular targets, we performed RNA sequencing of pre-treatment biopsies from 43 patients with operable TNBC who received neoadjuvant anthracycline and taxane-based chemotherapy. Ingenuity pathway analysis demonstrated that the top canonical pathway associated with higher likelihood of recurrence was higher expression of oxidative phosphorylation (OXPHOS) signature. We therefore sought to determine the efficacy of IACS-10759, a potent inhibitor of OXPHOS, in 10 TNBC patient-derived xenografts (PDX), 8 generated from chemotherapy-resistant tumors. Partial response was observed in one PDX model and prolonged disease stabilization in 5 of 10 PDXs. PDXs with higher expression of protein coding mitochondrial genes were more sensitive to IACS-10759. AXL overexpression was associated with intrinsic and acquired IACS-10759 resistance. The combination of cabozantinib, a multi-kinase inhibitor targeting AXL, with IACS-10759 significantly improved responses in TNBC PDXs. In contrast, selective AXL inhibitor BGB324 or knockdown of AXL did not enhance IACS-10759 sensitivity. In addition, an in vivo synthetic lethality screen identified CDK4, PARP1 and PARP2 as potential combination targets for IACS-10759. Palbociclib as well as talazoparib enhanced growth inhibitory effect of OXPHOS inhibition in vitro and in vivo. Our data suggests that OXPHOS is a promising target in chemoresistant TNBC. IACS-10759 is currently in Phase 1 testing, including TNBC. Further work is needed to determine the optimal biomarker-driven combination partners.
Citation Format: Kurt Evans, Stacy Moulder, Erkan Yuca, Stephen Scott, Natalia Paez Arango, Maryam Shariati, Christopher P Vellano, Turcin Saridogan, Xiaofeng Zheng, Ana Maria Gonzalez-Angulo, Ming Zhao, Xiaoping Su, Coya Tapia, Ken Chen, Argun Akcakanat, Charles M Perou, Bora Lim, Debu Tripathy, Timothy A Yap, Maria E Di Francesco, Giulio Draetta, Philip Jones, Joe Marszalek, Funda Meric-Bernstam. Oxidative phosphorylation is a metabolic vulnerability in chemotherapy resistant triple negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C016. doi:10.1158/1535-7163.TARG-19-C016
Abstract C046: A Smo inhibitor DCBCO1303 with potent Hedgehog signaling pathway antagonist activity is highly active in animal tumor model of medulloblastoma and cholangiocarcinoma
Authors: Lee Ying-Shuan E , Kuo Mann-Yan , Tsai Pei-Yi , Liu Chia Wei , Wei Win Yin 
Published: March 2020

Abstract
The hedgehog (Hh) pathway is a critical embryonic signaling cascade regulating cell growth, proliferation and differentiation. Hh signaling is significantly less active in adult tissues, where its primary role appears to be the maintenance of stem cell populations in skin and the central nervous system. Smoothened (Smo), a 7-pass transmembrane receptor with a GPCR-like structure, is a key component of the Hh signaling pathway, the activity of which is suppressed by the 12-pass transmembrane protein Patched (Ptch). Therefore, components of the Hh pathway (such as Shh, SMO, and GLI1/2) are viable therapeutic targets for anti-tumor strategy. We report here the in vivo effects of a potent Smo antagonist DCBCO1303 for the treatment of medulloblastoma and cholagiocarcinoma animal tumor model. DCBCO1303 demonstrated Hh signaling pathway antagonist activity in a 293 cell-based Gli-luciferase inhibition assay upon agonist treatment (IC50 = 3.5 nM), and retains inhibition activity against the Smo wild-type and D473H mutant responsible for resistance to GDC-0449 in medulloblastoma patients with IC50 of 5.1 and 43.7nM, respectively. DCBCO1303 potently suppress Gli1 expression in HEPM cells with IC50 of 2.3 nM. Treatment of a medulloblastoma allograft model with daily oral dosing from 1.25 to 40 mg/kg of DCBCO1303 for 10 days leads to dose responsive antitumor activity with tumor regressions occurring at 40 mg/kg.(Gli 1 mRNA inhibition correlated with tumor growth inhibition). DCBCO1303 was also highly efficacious against the growth of cholangiocarcinoma xenograft tumors. The DCBCO1303 can therefore be evaluated further and serve as a drug development candidate for treatment of Hh pathway-driven cancers.
Citation Format: Ying-Shuan E Lee, Mann-Yan Kuo, Pei-Yi Tsai, Chia Wei Liu, Win Yin Wei. A Smo inhibitor DCBCO1303 with potent Hedgehog signaling pathway antagonist activity is highly active in animal tumor model of medulloblastoma and cholangiocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C046. doi:10.1158/1535-7163.TARG-19-C046
Abstract C063: A novel Nrf2 inhibitor suppresses proliferation and enhances the sensitivity of cancer cells to chemotherapy
Authors: Zhang Di , Aldrich Kelly , Dexheimer Thomas , Ellsworth Edmund , Odom Aaron , Liby Karen 
Published: March 2020

Abstract
The Nrf2-Keap1-ARE pathway, a master defense mechanism against oxidative and electrophilic stresses, has emerged as a target for cancer therapy. Activation of Nrf2 has been a common strategy for cancer prevention, as Nrf2 deficiency enhances susceptibility to carcinogens in a wide variety of preclinical models. However, accumulating evidence suggests a tumor-promoting role for Nrf2 in established tumors. Constitutive activation of Nrf2 because of gain of functionmutations in NFE2L2 or loss of function mutations in its negative regulator Keap1, has been found in many cancers, especially lung cancer, and is associated with chemoresistance and poor survival in human patients. Nrf2 inhibitors, therefore, provide a potential novel strategy for treating cancer. Here, we report a novel Nrf2 inhibitor, MSU225, identified from an existing chemistry library. MSU225 dose-dependently downregulated tBHQ (tert-butyl hydroquinone)-induced Nrf2 transcriptional activity in a luciferase reporter assay without cytotoxicity. MSU225 also decreased the expression of Nrf2 downstream targets, including HO-1, NQO1, GST1A1, GCLC, GCLM, and UGT1A6 in A549 human lung cancer cells, in which Keap1 is mutated and Nrf2 activation is constitutive. Notably, MSU225 induced a striking and significant (p&lt;0.05) decrease of Nrf2 protein in A549 cells. The effect of MSU225 on Nrf2 protein levels can be blocked with the proteasome inhibitor MG132, suggesting MSU225 enhances Nrf2 degradation through the proteasome system. Ubiquitination of Nrf2 was also increased after MSU225 treatment. Interestingly, MSU225 also decreased Nrf2 protein levels in Keap1 knockout and βTrCP knockout cells, which are the two major pathways inducing Nrf2 degradation. Nrf2 involvement in cancer cell proliferation is well known. MSU225 inhibited the growth of human lung cancer cells (A549, H460, A427) in both 2D cell culture and soft agar. Cells addicted to Nrf2 were more susceptible to MSU225 suppression of cell proliferation than cells not addicted to Nrf2. MSU225 also sensitized A549 cells to chemotherapies including doxorubicin, carboplatin, 5-fluorouracil and Topotecan. Our results suggest that MSU225 is a novel Nrf2 inhibitor that enhances the degradation of Nrf2 in a Keap1 and βTrCP independent manner. In vivo studies to assess the efficacy of MSU225 for treating experimental lung cancer are ongoing.
Citation Format: Di Zhang, Kelly Aldrich, Thomas Dexheimer, Edmund Ellsworth, Aaron Odom, Karen Liby. A novel Nrf2 inhibitor suppresses proliferation and enhances the sensitivity of cancer cells to chemotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C063. doi:10.1158/1535-7163.TARG-19-C063
Abstract C066: BT5528, a Bicycle Toxin Conjugate targeting EphA2: mechanism of action and clinical translation
Authors: Bennett Gavin , Brown Amy , Mudd Gemma , Lahdenranta Johanna , Keen Nicholas 
Published: March 2020

Abstract
BT5528 is a Bicycle Toxin Conjugate (BTC) in which an EphA2 binding peptide (a Bicycle®) is conjugated through an inert sarcosine spacer chain, and a cleavable linker, to the antimitotic toxin MMAE. Increased EphA2 expression has been reported in multiple tumor types (including NSCLC, ovarian cancer, TNBC, gastric/upper GI, pancreatic and urothelial cancers) and so represents a attractive tumor binding target. The identification, characterization and initial in vivo profiling of BT5528 has previously been described. This abstract describes a more detailed analysis of the mechanism of action of BT5528. Dosing of BT5528 on a once weekly schedule is efficacious in a range of tumour models. Observed anti-tumor activity is closely related to the level of EphA2 expression on tumor cells ranging from complete responses in EphA2 positive models to minimal activity in EphA2 low/null models. Efficacy of BT5528 is also seen in a number of “hard to hit” models including large (~1000mm3) patient derived xenograft models (PDX) including highly-resistant models and PDX models of pancreatic ductal adenocarcinoma. We also demonstrate the utility of BT5528 in disseminated disease in an EphA2 positive model of bone metastasis. Efficacy of BT5528 is seen even when dosed as infrequently as every 2 weeks and is not dependent on infusion duration allowing for flexible drug administration schedule. Additionally, we demonstrate the significance of the BT5528 bystander effect to anti-tumor activity using versions of BT5528 with non-releasable payload as well as non-cell permeable payload. Efficacy of BT5528 is also seen in a number of “hard to hit” models including large (~1000mm3) PDX, highly-resistant models, models of pancreatic cancer, and models of metastatic disease. Importantly, BT5528 can produce this profound efficacy without the bleeding and coagulation toxicity seen with previous ADC approaches to this target. The overall profile of BT5528 provides a highly differentiated approach to targeting EphA2, offering the potential for profound efficacy in a range of solid tumours. IND-enabling activities are underway, with clinical trials expected to start later this year.
Citation Format: Gavin Bennett, Amy Brown, Gemma Mudd, Johanna Lahdenranta, Nicholas Keen. BT5528, a Bicycle Toxin Conjugate targeting EphA2: mechanism of action and clinical translation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C066. doi:10.1158/1535-7163.TARG-19-C066
Abstract C067: Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA
Authors: Gu Long , Li Min , Lingeman Robert , Hickey Robert J , Liu Yilun , Malkas Linda H 
Published: March 2020

Abstract
Proliferating cell nuclear antigen (PCNA), through its interaction with various proteins involved in DNA synthesis, cell cycle regulation, and DNA repair, plays a central role in maintaining genome stability. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was predominantly expressed in a broad range of cancer cells and tumor tissues, but not significantly in non-malignant cells. We found that the caPCNA-specific antigenic site lies between L126 and Y133, a region within the interdomain connector loop of PCNA that is known to be a major binding site for many of PCNA’s interacting proteins. A cell permeable peptide harboring the L126-Y133 sequence inhibited PCNA function in cancer cells and selectively kills cancer cells and xenograft tumors. Based on these observations, we sought small molecules targeting this peptide region of PCNA as potential broad-spectrum anti-cancer agents. Our effort led to a drug candidate, AOH1996, which selectively kills a broad range of cancer cells at high nanomolar concentrations, but is not associated with significant toxicity to non-malignant cells. It also works synergistically with DNA damaging chemotherapeutic drugs, such as cisplatin and irinotecan, to selectively kill cancer cells. This compound is orally available to animals and suppresses tumor growth in a dosage form compatible to clinical applications. Importantly, it doesn’t cause significant toxicity at 2.5 times its effective dose. Mechanistically, AOH1996 competes with T3, a known PCNA ligand, for binding to PCNA. However, the mechanism by which AOH1996 exerts its effect on cancer cells may not be identical to what have been reported for the T3 analogs. In particular, we found that AOH1996 interferes with the association of PCNA and its binding proteins, leading to DNA replication stress, blockade of homologous recombination-mediated DNA repair, and induction of apoptosis in cancer cells. These findings demonstrated the potential of this compound as a novel therapeutic agent warranting clinical investigation for cancer treatment. We have started planning a phase 1 clinical study for this compound.
Citation Format: Long Gu, Min Li, Robert Lingeman, Robert J Hickey, Yilun Liu, Linda H Malkas. Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C067. doi:10.1158/1535-7163.TARG-19-C067