bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract CT116: Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed, MGMT-unmethylated glioblastoma
Authors: Chen Zhong-ping , Guo Chengcheng , Bacha Jeffrey , Langlands John , Steino Anne , Kwan Claire , Kanekal Sarath , Schwartz Richard , Lopez Lorena , Brown Dennis
Published: August 2019

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemo-radiation and temozolomide. An unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance and is strongly correlated with poor outcomes. Unmethylated MGMT represents the majority of newly diagnosed GBM tumors. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as single agent and in combination with radiotherapy. VAL-083 induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083’s unique mechanism-of-action circumvents MGMT-mediated chemoresistance, and it has demonstrated cytotoxicity in MGMT-unmethylated GBM cell-lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. We completed a dose-escalation trial of VAL-083 in recurrent GBM, and a generally well-tolerated dosing regimen was selected for further clinical development. The present trial is an ongoing open-label, biomarker-driven, Phase I/II study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study is being conducted in two parts. The dose-confirmation part (20, 30, and 40 mg/m2/day IV infusion on days 1-3 of a 21-day cycle) has been completed, and the expansion part has been initiated in up to 20 additional patients at 30 mg/m2/day IV infusion on days 1-3 of a 21-day cycle. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. Trial design, enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736.

Citation Format: Zhong-ping Chen, Chengcheng Guo, Jeffrey Bacha, John Langlands, Anne Steino, Claire Kwan, Sarath Kanekal, Richard Schwartz, Lorena Lopez, Dennis Brown. Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed, MGMT-unmethylated glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT116.
Abstract CT152: A Phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC)
Authors: Borazanci Erkut H. , Jameson Gayle , Korn Ronald Lee , Caldwell Lana , Ansaldo Karen , Hendrickson Kristin , Marceau Katie , Gosselin Kevin , Hoff Daniel D. Von
Published: August 2019

Background: Effective therapy for the treatment of PDAC remains one of the greatest unmet oncology clinical needs. The addition of C to G and AP has shown promising clinical data in a previously reported study [J Clin Oncol 35, 2017 (suppl 4S; abstract 341)]. In preclinical work, vitamin D (Vit D) analog therapy decreases myeloid derived suppressor cells and regulatory T cells, favorably influencing the immune environment. This trial combines AP/C/G with Vit D analog P and the anti-PD-1 antibody N as a combination therapy for patients with previously untreated metastatic PDAC. This trial evaluates the efficacy and safety of NAPPCG in that patient population (NCT02754726).

Methods: Eligibility criteria include Stage IV PDAC, no prior chemotherapy for systemic disease, KPS ≥ 70, and measurable disease. Doses are AP 125 mg/m2 undiluted, G 1000 mg/m2 in 250 ml of normal saline (NS), each infused over 30 minutes with C 25 mg/ m2 in 500 ml of NS infused over 60 minutes on days 1, 8, 22, and 29 of a 42-day cycle. N is given at a fixed dose of 240 mg as a 60 minute infusion on days 1, 15, and 29. P is given at a fixed dose of 25 µg IV twice weekly. Primary objective is to determine the efficacy of the combination for patients with previously untreated metastatic PDAC through determining CR, ORR, PFS, and OS. The secondary objective is to evaluate safety in patients with previously untreated metastatic PDAC.

Results: Trial was initiated May 2016 and 25 patients have been enrolled in the study and 24 are evaluable (baseline and ≥1 follow up CT scan). Most common drug-related grade (Gr) 3-4 adverse events (AE’s), are thrombocytopenia 76% (gr 3 = 44%, gr 4 = 32%) with no serious bleeding events, anemia 44% (gr 3 = 44%, gr 4 = 0%), and colitis 12% (gr 3 = 12%, gr 4 = 0%). By RECIST 1.1 criteria, response is 19 PR, 2 SD, 2 PD, yielding an 83% ORR. Median PFS is 8.17 months. Median OS is 15.3 months.

Conclusions: Although a small study, the high response rate is encouraging. The clinical trial is now being expanded. Supported by grants from the Seena Magowitz Foundation, Mattress Firm, Bristol Myers Squibb, and SU2C.

Citation Format: Erkut H. Borazanci, Gayle Jameson, Ronald Lee Korn, Lana Caldwell, Karen Ansaldo, Kristin Hendrickson, Katie Marceau, Kevin Gosselin, Daniel D. Von Hoff. A Phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT152.
Abstract CT172: Phase III METIS study: Tumor Treating Fields (150 kHz) and radiosurgery for supra- and/or infratentorial brain metastases (1-10) from non-small cell lung cancer (NSCLC)
Authors: Mehta Minish P , Gondi Vinai , Ahluwalia Manmeet , Brown Paul D.
Published: August 2019

Background: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising low intensity alternating electric fields. TTFields has demonstrated efficacy in non-small cell lung cancer (NSCLC) in in vitro and in vivo models, and in a Phase I/II clinical study. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. This prospective, multicenter study [NCT02831959] investigated the efficacy, safety and neurocognitive outcomes of TTFields in NSCLC patients with brain metastases.

Methods: NSCLC patients (N=270) with 1-10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays and allows normal daily activities. Patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Patients in the control arm are allowed to cross over to TTFields arm at the time of second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2-10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1-4 and 5-10 brain metastases; bi-monthly intracranial progression rate from 2-12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.

Citation Format: Minish P Mehta, Vinai Gondi, Manmeet Ahluwalia, Paul D. Brown. Phase III METIS study: Tumor Treating Fields (150 kHz) and radiosurgery for supra- and/or infratentorial brain metastases (1-10) from non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT172.
Abstract CT175: HEPANOVA Phase II study design for advanced hepatocellular carcinoma: Tumor treating fields concomitant with sorafenib
Authors: Grosu Anca-Ligia , Gkika Eleni , Brunner Thomas , Thimme Robert , Weinberg Uri
Published: August 2019

Background Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of hepatocellular carcinoma (HCC), leading to a significant increase in cell death. The Phase II HEPANOVA study is the first trial testing TTFields in HCC patients, and is designed to test the safety and efficacy of adding TTFields to sorafenib in advanced HCC.

Methods Trial Design: Patients (N=25) with unresectable HCC who are not amenable to any local treatment will be enrolled in this prospective, single-arm study. The study enrolls patients with ECOG score of 0-2 and Barcelona clinic liver cancer (BCLC) stage 0-C. Patients must have a measurable disease per RECIST Criteria. Having implanted electronic devices in the torso is exclusionary. Sorafenib will be administered at standard dose (400 mg daily). TTFields (150 kHz) will be delivered for 18 hours/day until local disease progression per RECIST Criteria. Clinical follow up will be performed q4w, and a CT/MRI scan q12w. Following disease progression in the liver, patients will discontinue TTFields and be followed monthly for survival. Overall response rate will be the primary endpoint and in-field control rate, progression-free survival rate at 12 month (PFS12), OS rate at 1 year and toxicity will all be secondary endpoints. Sample size was calculated using an Exact test for proportions considering the weighted average of ORR of patients who had either complete or partial response per RECIST criteria in historical studies with sorafenib is 4.5%. A sample size of 25 patients was required to achieve a power of approximately 80% at a one-sided alpha level of 0.05 using a single sample Exact test for proportions.

Citation Format: Anca-Ligia Grosu, Eleni Gkika, Thomas Brunner, Robert Thimme, Uri Weinberg. HEPANOVA Phase II study design for advanced hepatocellular carcinoma: Tumor treating fields concomitant with sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT175.
Abstract LB-002: SQ3370 enhances the safety of chemotherapeutics via local activation therapy
Authors: Yee Nathan A. , Srinivasan Sangeetha , Royzen Maksim , Oneto Jose M. Mejia
Published: August 2019

With systemic chemotherapy, only 1-2% of the administered dose actually reaches a localized tumor, while the remaining leads to adverse off-target toxicities, including immunosuppression. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our patented approach (SQ3370) consists of:

(1) SQL70 - a drug-activating biomaterial carrying no payload

(2) SQP33 - a chemically-modified prodrug of doxorubicin (Dox) with attenuated activity.

SQL70 is injected at the tumor site followed by SQP33 administered systemically. The prodrug first concentrates to the biomaterial at the tumor site due to their complementary chemical reactivities. The active drug is then spontaneously released over multiple days, providing sustained local delivery directly to the tumor region while reducing systemic side effects.

Previously, we have shown that the greater safety of SQP33 allows it to be given at over 38 times the dose of standard Dox in SQL70-injected mice. Pharmacokinetic and biodistribution studies in SQ3370-treated rodents and dogs show that SQP33 disappears from plasma within the first hour of administration, likely due to the rapid concentration to SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to activated Dox. These studies also indicate that a single injection of SQL70 can activate multiple doses of SQP33, maximizing the local therapeutic index.

Recent studies demonstrate that SQ3370 treatment enhances therapeutic response and survival in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 slowed tumor progression in 8/10 mice, showing improved efficacy compared to standard Dox or anti-PD-1 therapy.

In mice bearing dual tumors, with one tumor site injected locally with SQL70, we observed that SQP33 can induce a response in both primary and secondary tumors, suggestive of an anti-tumor immune activation effect. Furthermore, we found that SQ3370 synergizes with anti-PD-1, expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy.

Collectively, our results demonstrate that SQ3370 enables delivery of cytotoxic drugs to a target site while limiting exposure in off-target tissues in small and large animals, leading to improvements in both safety and efficacy.

Citation Format: Nathan A. Yee, Sangeetha Srinivasan, Maksim Royzen, Jose M. Mejia Oneto. SQ3370 enhances the safety of chemotherapeutics via local activation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-002.
Abstract LB-016: Radiochemotherapy combined with NK cells followed by a second-line PD-1 inhibition in a patients with NSCLC stage IIIb induces long-term tumor control
Authors: Multhoff Gabriele , Kokowski Konrad , Hildebrandt Martin , Vaupel Peter , Stangl Stefan
Published: August 2019

Advanced stage NSCLC is a fatal disease with poor prognosis. Following radiochemotherapy (RCT) tumor progression occurs after 5.6 months in stage III NSCLC patients. We identified membrane heat shock protein 70 (mHsp70) as a biomarker for high-risk NSCLC. Furthermore, mHsp70 serves as a tumor-specific target for NK cells that had been stimulated with Hsp70-peptide (TKD) and IL-2. In this study, a patient with mHsp70 positive inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated for the first time with a combined therapy consisting of RCT (64.8 Gy), 4 cycles of mHsp70-targeting, autologous NK cells and PD-1 antibody, as a second-line therapy.

Adoptive transfer of ex vivo Hsp70-activated NK cells after RCT combined with PD-1 inhibition was well tolerated and resulted in a superior OS. No viable tumor cells, but a massive immune cell infiltration of T and NK cells in fibrotic tissue were detected after therapy. Neither tumor progression nor distant metastases were detectable by CT-scanning 35 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell, CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. In summary, a combined immunotherapy consisting of RCT, mHsp70-targeting NK cells and PD-1 antibody inhibition is well tolerated, induces anti-tumor immune responses and results in long-term tumor control in a patient with advanced NSCLC.

Citation Format: Gabriele Multhoff, Konrad Kokowski, Martin Hildebrandt, Peter Vaupel, Stefan Stangl. Radiochemotherapy combined with NK cells followed by a second-line PD-1 inhibition in a patients with NSCLC stage IIIb induces long-term tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-016.
Abstract LB-018: Orally active small molecule PD-L1 inhibitor demonstrating similar efficacy as Durvalumab in human knock-in MC38 model
Authors: Wang Yuguang , Zhang Nong , Wang Feilan , Zhao Qiang , Li Zenggang
Published: August 2019

Cancer immunotherapy with PD-1/PD-L1 antibody drugs has made tremendous progress in clinical application. It was also recognized by the scientific community with awarding of the 2018 Nobel Price. However, the discovery of orally active, small molecule drugs targeting PD-1/PD-L1 pathway remains highly challenging. We wish to report for the first time the similar efficacy as measured by TGI between small molecule inhibitor Max-10181 and Durvalumab in the head to head test of human PD-L1 knock-in MC38 cell line in human PD-1 knock-in mice. In addition, we would also like to report the superior efficacy of Max-10181 to mouse anti-PD-1 Ab in PD-L1 expression low syngeneic mouse 4T1 model. Our data indicated that small molecule drugs may have different dependency of PD-L1 expression level. As a result, they may have different therapeutic application in clinics. Furthermore, the data related to the mechanistic aspect of these observed results will also be discussed.

Citation Format: Yuguang Wang, Nong Zhang, Feilan Wang, Qiang Zhao, Zenggang Li. Orally active small molecule PD-L1 inhibitor demonstrating similar efficacy as Durvalumab in human knock-in MC38 model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-018.
Abstract LB-027: Evaluation of EGFR induced on-target and target-mediated adverse effects in a 3D human lung tumour/skin microphysiological co-culture system
Authors: Huebner Juliane , Raschke Marian , Schimek Katharina , Ruetschle Isabel , Graessle Sarah , Schnurre Susanne , Lauster Roland , Maschmeyer Ilka , Steger-Hartmann Thomas , Marx Uwe
Published: August 2019

Organs-on-a-chip or microphysiological systems (MPS) are increasingly contributing to the preclinical characterization of mode of action and adverse events of drug candidates. The recent advent of robust human multi-organ-chip systems enables the establishment of co-cultures of human drug target tissues with healthy organ equivalents prone to off-target effects of the respective drug. The prediction of side effects, such as those occurring in the skin during cancer therapies with antibodies against the epithelial growth factor receptor (EGFR), is currently not possible in conventional in vitro systems and limited in existing animal models due to phylogenetic differences between species.

Here we present a chip-based 5-day co-culture of human lung tumour spheroids (mucoepidermoid carcinoma H292) and human skin equivalents. We investigated the impact of repeated cetuximab exposure, an antibody against the EGF receptor to the co-culture and compared it with the effects on individual tissue cultures. Cetuximab showed an increased pro-apoptotic related gene expression in the tumor microtissues, and, simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated. Additionally, we compared the tumor-target related antibody effects with response data for afatinib - a small molecule EGFR inhibitor. Cetuximab showed an increased pro-apoptotic related gene expression in the tumor microtissues, and, simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated.

The described MPS has the potential to provide a single platform for in vitro evaluation of the therapeutic window of drug candidates.

Citation Format: Juliane Huebner, Marian Raschke, Katharina Schimek, Isabel Ruetschle, Sarah Graessle, Susanne Schnurre, Roland Lauster, Ilka Maschmeyer, Thomas Steger-Hartmann, Uwe Marx. Evaluation of EGFR induced on-target and target-mediated adverse effects in a 3D human lung tumour/skin microphysiological co-culture system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-027.
Abstract LB-029: Identification of predictive genetic signatures of Cytarabine responsiveness in acute myeloid leukemia using a novel 3D translational culture model of primary bone marrow
Authors: Xu Haiyan , Muise Eric S. , Javaid Sarah , Chen Lan , Cristescu Razvan , Mansueto My Sam , Follmer Nicole , Cho Jennifer , Kerr Kimberley , Altura Rachel , Machacek Michelle , Nicholson Benjamin , Addona George , Kariv Ilona , Chen Hongmin
Published: August 2019

Acute myeloid leukemia (AML) is a malignancy with complex genetics, poor survival rates and high rates of chemotherapy resistance. This study reports the establishment of a novel bone marrow mononuclear cell 3D-culture model and the application of this model to define sensitivity and resistance biomarkers as evident by DNA and RNA expression signatures in response to standard Cytarabine (Ara-C) chemotherapy. By simulating the bone marrow microenvironment, we optimized the growth conditions using frozen bone marrow mononuclear cells (BMMC) derived from healthy donors. We validated our platform by demonstrating that healthy BMMCs are capable of differentiating into all hematopoietic lineages and various types of stromal cells. Using this platform, we then characterized BMMC samples from 47 AML patients. Sixty percent of AML samples were capable of proliferating and 23 samples demonstrated robust growth. RNA sequencing was performed for 3D and 2D cultures to determine which conditions are superior at maintaining original gene expression signatures as compared to the uncultured bone marrow, To elucidate specific genetic mutations and/or gene expression signatures associated with the ability of ex vivo growth of these AML donors, whole exosome sequencing and RNA Sequencing were performed. The model identified unique gene expression signatures that correlated with sensitive as well as resistant donors in response to Ara-C treatment. These data demonstrate the translational value of our platform which should be widely applicable to evaluate other therapies in AML.

Citation Format: Haiyan Xu, Eric S. Muise, Sarah Javaid, Lan Chen, Razvan Cristescu, My Sam Mansueto, Nicole Follmer, Jennifer Cho, Kimberley Kerr, Rachel Altura, Michelle Machacek, Benjamin Nicholson, George Addona, Ilona Kariv, Hongmin Chen. Identification of predictive genetic signatures of Cytarabine responsiveness in acute myeloid leukemia using a novel 3D translational culture model of primary bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-029.
Abstract LB-041: Targeting AKT2 and ERK decline the drug/radiation resistance in neuroblastoma
Authors: Kim Kwang Woon , Chung Dai , Qiao Jingbo , Kim Julia , Poewers Camille , Correa Hernan , Park Kyungho , Lee Sora
Published: August 2019

Introduction: Neuroblastoma is highly heterogeneous, containing cancer cells with very different molecular characteristics. Activation of distinct signal transduction pathways can induce neuroblastoma cells to transform cells with neuronal, chromaffin, or schwannian phenotypes, further supporting the existence of cancer stem cells. We previously demonstrated that AKT2 plays critical roles in regulation of neuroblastoma tumorigenesis. Here we hypotheize that targeting AKT2 would block the signal transduction pathways enhanced in drug/radiation resistant neuroblastoma cancer stem cells.

Methods: We generated cisplatin (CDDP) resistant and radiation (Rad) resistant neuroblastoma cells under the treatment or irradiation with a concentration of IC 50 of CDDP and 137Cs irradiator respectively. Cell viability was assessed with CCK-8 kit daily. Extreme limiting dilution analysis (ELDA) was performed for quantification of tumor sphere formation. Immunoblotting detected the expression of stem cell markers CD133, Sox2, ALDH, ALDH, Nestin, Oct4 and Nanog, as well as survival signaling pathway key molecules AKT2, MAPK and P38 MAPK.

Results: We founded that two important cell proliferation and survival signaling pathways mTOR, downstream of AKT2 and MAPK enhanced in CDDP-resistant and Rad-resistant neuroblastoma cells. Blocking these two pathways with chemical inhibitors, CCT128930, AKT2 selective inhibitor and PD98059, MEK inhibitor decreased cell proliferation, angiogenesis, cell migration and soft agar conoly growth in these resistant cells. We further demonstrated that these resistant cells showed higher capacity of sphere-forming with increased expression of stem cell markers CD133, Sox2, ALDH, ALDH, Nestin, Oct4 and Nanog. Improtantly, the sphere formation of these resistant cells is sensitive to the inhibitors of AKT2 and MAPK.

Conclusion: Our results suggest that selected CDDP-resistant and radiation-resistant neuroblastoma cells might serve as an useful tool to improve understanding of the molecular mechanisms of therapeutic resistance and develop more effective novel treatment strategies, and further to reaching better clinical outcomes of patients with neuroblastoma.

Citation Format: Kwang Woon Kim, Dai Chung, Jingbo Qiao, Julia Kim, Camille Poewers, Hernan Correa, Kyungho Park, Sora Lee. Targeting AKT2 and ERK decline the drug/radiation resistance in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-041.
Abstract LB-065: A high quality neoantigen fitness model cooperates with T lymphocyte infiltrates to identify glioblastoma patients with the longest survival
Authors: Zhang Jing , Caruso Francesca P. , Sa Jason K. , Justesen Sune , Nam Do-Hyun , Sims Peter , Ceccarelli Michele , Lasorella Anna , Iavarone Antonio
Published: August 2019

Malignant glioma (glioblastoma, GBM) is a lethal cancer resistant to multimodality therapeutic approaches. A high burden of tumor-specific mutant peptides (neoantigens) correlates with a more favorable prognosis and response to immunotherapies in selected solid tumors but the role of neoantigens and how they impact clinical outcome in most tumors including GBM remains unclear. Here, we exploited the similarity between tumor neoantigens and infectious disease-derived immune epitopes and applied a neoantigen fitness model for the identification of high quality neoantigens in human GBM. The neoantigen quality fitness model stratified GBM patients with more favorable clinical outcome and, together with tumor infiltration of CD8 T lymphocytes, identified a subgroup of GBM patients with the longest survival, thus exhibiting optimal performance. Conversely, neither tumor neoantigen burden from a quantity model nor the isolated enrichment of CD8 T lymphocytes could predict better survival of GBM patients. The GBM subgroup that emerged from the neoantigen quality model displays distinct genomic and transcriptomic features that should guide patient stratification for immunotherapy and maximal benefit of GBM patients.

Citation Format: Jing Zhang, Francesca P. Caruso, Jason K. Sa, Sune Justesen, Do-Hyun Nam, Peter Sims, Michele Ceccarelli, Anna Lasorella, Antonio Iavarone. A high quality neoantigen fitness model cooperates with T lymphocyte infiltrates to identify glioblastoma patients with the longest survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-065.
Abstract LB-092: TKI insensitive role of EGFRconfers TKI resistance via PKCδ
Authors: Lee Pei-chih , Hung Mien-chie
Published: August 2019

EGFR TKI-insensitive pathway confers heterogeneous mechanisms of TKI resistance via PKCδ in EGFR-mutant lung cancer. Multiple mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of EGFR heterodimer-mediated nuclear PKCδ as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is upregulated in a significant portion of patients (~41.5%) with TKI-resistant NSCLC and is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations. These results provide mechanistic insights into the role of the EGFR-PKCδ axis in TKI-resistance and suggest an EGFR addiction in TKI-resistant EGFR-mutant NSCLC.

Citation Format: Pei-chih Lee, Mien-chie Hung. TKI insensitive role of EGFRconfers TKI resistance via PKCδ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-092.
Abstract LB-103: Defining oncogenic SWI/SNF complex mediated immune reprogramming in squamous cell carcinoma
Authors: Saladi SrinivasVinod , Morris Robert , Ross Kenneth , Karaayvaz mihriban , Tata Purushothama Rao , mou hongmei , Rajagopal Jayaraj , Lawrence Michael , Ellisen Leif
Published: August 2019

Squamous cell carcinoma (SCC) remains among the most treatment-refractory of human cancers, reflecting in part a limited understanding of the key pathways and mechanisms that drive this disease. The p53-related transcription factor p63 is a central tumor maintenance factor subject to overexpression and/or genomic amplification in a high fraction of SCCs. Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. We reveal that ACTL6A, encoding a SWI/SNF subunit linked to stem and progenitor cell function, is frequently co-amplified and highly expressed together with p63 in head and neck, and lung squamous cell carcinoma (HNSCC & LUSC). ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. In vivo, ectopic ACTLC6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. More recently, we show the major cell-autonomous pathway repressed by ACTL6A is the interferon response in vitro, while we find ACTL6A amplification in HNSCC is associated with immunologically “cold” tumors despite a high mutation burden in vivo. Collectively, these findings reveal that ACTL6A orchestrates a tumor cell-intrinsic mechanism of immune evasion and define ACTL6A as a potent driver of human SCC.These findings establish a fundamental mechanism for ACTL6A and p63 to alter epigenetic states, and uncover a critical oncogenic function for SWI/SNF, which has been largely viewed as a tumor suppressor in human cancer. Furthermore, by revealing the Hippo-YAP pathway as a major target of ACTL6A/p63 linked to tumor behavior, this work suggests potential therapeutic approaches for refractory HNSCC cases.

Citation Format: SrinivasVinod Saladi, Robert Morris, Kenneth Ross, mihriban Karaayvaz, Purushothama Rao Tata, hongmei mou, Jayaraj Rajagopal, Michael Lawrence, Leif Ellisen. Defining oncogenic SWI/SNF complex mediated immune reprogramming in squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-103.
Abstract LB-106: Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology
Authors: Spycher Philipp Rene , Frei Julia Carina , Wehrmüller Jöri Elias , Attinger-toller Isabella , Grabulovski Dragan , Hechler Torsten , Kulke Michael , Pahl Andreas , Behe Martin , Schibli Roger
Published: August 2019

We introduce a novel and versatile ADC-linker technology that is based on site-specific enzymatic payload conjugation to ‘off-the-shelf’ antibodies, i.e., without the need to reduce or engineer the antibody. The functionalization takes place site-specifically and stoichiometrically (drug-to-antibody ratio, DAR = 2.0) at the Fc-part of antibodies. The resulting ADCs show favorable biophysical properties such as high solubility and stability using different payloads. Additionally, initial ELISA findings show that our modification does not interfere with Fc-gamma receptor and FcRn binding. Importantly, our ADCs showed superior efficacy in different tumor animal models as compared to control Thiomab™ ADCs. Using native trastuzumab (non-engineered) as the targeting antibody and amanitin as payload, we generated within 36 hours highly homogeneous and pure ADCs with a well-defined DAR of 2.0 as confirmed by LC-MS. In in-vitro assays our ADCs demonstrated potent cytotoxicity in all tested cell-lines (SKBR-3, BT-474, JIMT-1, and NCI-N87) as compared to the control Thiomab™ ADCs, most strikingly for the JIMT-1 cell-line: EC50 of 0.15nM vs 2.5nM. In the mouse JIMT-1 tumor model, our anti-HER2 ADC was highly potent and resulted in complete tumor remission in all mice (10/10 mice) at a single dose of 2mg/kg. In contrast, the control Thiomab™-functionalized ADC showed tumor regrowth in 4 out of 10 animals, starting on day 50. The same high potency was observed for the NCI-N87 xenograft model at a dose of 3mg/kg in which tumor growth inhibition was significantly delayed versus the reference ADC (8/10 vs 4/10 animals alive on day 110). These encouraging results obtained so far indicate that our linker technology a) allows for fast (< 36 hours) and straightforward manufacturing of ADCs using different payloads without protein engineering efforts, b) results in ADCs with favorable biophysical properties and a clear defined drug-to-antibody ratio, and c) enables the generation of highly potent and stable, thus safer, next-generation ADCs.

Citation Format: Philipp Rene Spycher, Julia Carina Frei, Jöri Elias Wehrmüller, Isabella Attinger-toller, Dragan Grabulovski, Torsten Hechler, Michael Kulke, Andreas Pahl, Martin Behe, Roger Schibli. Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-106.
Abstract LB-110: Proteasome addiction a new therapeutic opportunity to treat PTEN-deficient brain tumors
Authors: Benitez Jorge A. , Finlay Darren , Rosa-Campos Alexandre , Ma Jianhui , Koga Tomoyuki , Vuori Kristiina , Furnari Frank
Published: August 2019

One of the most common genetic alterations in glioblastoma (30-40%) occurs in the tumor suppressor gene PTEN (phosphatase and tensin homolog), where loss of function has been mechanistically linked to increased tumor cell invasion, and to a lack of radio- and chemo-therapy response. To identify new drug compounds that target PTEN-deficient brain tumors we performed a high throughput drug screening using patient-derived GBM spheres and found that PTEN-deficient samples were highly sensitive to proteasome inhibitors. We confirmed PTEN dependency to proteasome inhibition by genetically overexpressing or deleting PTEN in GBM cells and established that the drug inhibition response relied on PTEN enzymatic activity. Additionally, proteasome inhibition specifically suppressed tumor growth and increased survival of mice orthotopically engrafted with human PTEN-null glioblastoma cancer stem cells. Mechanistically, we determined that PTEN-deficient cells were more sensitive to proteasome inhibition due to an increase in protein synthesis rate and loss of autophagy activity associated with activation of the PI3K/mTOR pathway. Finally, integrated in silico analysis of the Samsung Medical Center dataset corroborated that samples with PTEN/EGFR/PI3K alterations were significantly more sensitive to Carfilzomib, an FDA-approved proteasome inhibitor. This study reveals that PTEN-deficient cells are "proteasome addictive" and opens a new therapeutic opportunity to treat glioblastoma PTEN-deficient patients.

Citation Format: Jorge A. Benitez, Darren Finlay, Alexandre Rosa-Campos, Jianhui Ma, Tomoyuki Koga, Kristiina Vuori, Frank Furnari. Proteasome addiction a new therapeutic opportunity to treat PTEN-deficient brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-110.
Abstract LB-113: MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability inBRAF,NRASandNF1-mutant melanomas
Authors: Maertens Ophélia , Kuzmickas Ryan , Manchester Haley , Emerson Chloe , Gavin Alessandra , Guild Caroline , Wong Terence , Raedt Thomas De , Bowman-Colin Christian , Hatchi Elodie , Garraway Levi , Flaherty Keith , Pathania Shailja , Elledge Stephen , Cichowski Karen
Published: August 2019

While the majority of BRAF-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in NRAS and NF1-mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three Ras pathway-driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, both in models that are sensitive or relatively resistant to these agents. Interestingly, MGMT expression predicts responsiveness and marks tumors with latent defects in DNA repair. BRAF/MEK inhibitors enhance these defects by suppressing homologous recombination genes, inducing a BRCA-like state; however, entinostat addition triggers the concomitant suppression of NHEJ genes, resulting in a chemical synthetic lethality caused by excessive DNA damage. Together these studies identify melanomas with latent DNA repair defects, describe a promising drug combination that capitalizes on these defects, and reveal a tractable therapeutic biomarker.

Citation Format: Ophélia Maertens, Ryan Kuzmickas, Haley Manchester, Chloe Emerson, Alessandra Gavin, Caroline Guild, Terence Wong, Thomas De Raedt, Christian Bowman-Colin, Elodie Hatchi, Levi Garraway, Keith Flaherty, Shailja Pathania, Stephen Elledge, Karen Cichowski. MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability inBRAF,NRASandNF1-mutant melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-113.
Abstract LB-120: Acetylated Kruppel-like factor 5 and transforming growth factor-β mediated drug resistance in prostate cancer
Authors: Li Yixiang , Zhang Baotong , Dong Jin-Tang
Published: August 2019

Purpose: In this study, we explored the role of Kruppel-like factor 5 (KLF5) and its acetylated form on lysine 369 in transforming growth factor-β (TGFβ) induced drug resistance to promote antitumor synergy and overcome drug resistance in advanced stage prostate cancer. Procedures: Two aggressive prostate cancer cell lines DU 145 and PC-3 were treated with docetaxel to measure cytotoxicity. To assess docetaxel resistance, we used in-vitro cell survival assay, colony survival assay and xenograft mouse model. In addition, TGFβ1 and SB505124 (TGFβ receptor I inhibitor) were used to explore TGFβ induced docetaxel resistance. To measure function of KLF5 and its different acetylation form on lysine 369, stable cell lines were constructed with different KLF5 acetylation status mimics after knocking out endogenous KLF5, utilizing the CRISPR-Cas9 system.

Results: We found that KLF5 alone induced docetaxel resistance in vivo, but not in vitro. Moreover, endogenous knocking out of KLF5 inhibited TGFβ induced docetaxel resistance. In addition to previous findings that TGFβ recruits P300 acetyl-transferase to acetylate KLF5 on lysine 369, we further found that TGFβ induced docetaxel resistance depends on acetylation of KLF5. In addition, Mass Spectrometry analysis revealed that JUNB, a downstream target of non-canonical TGFβ pathway, is a direct binding target of acetylated KLF5 but not de-acetylated KLF5. Knocking down of JUNB in acetylated KLF5 mimic cell line inhibited TGFβ induced docetaxel resistance.

Conclusions: These suggested that acetylated KLF5 is indispensable in TGFβ induced drug resistance through interaction with JUNB. Our study introduced a novel mechanism of acetylated KLF5 and JUNB mediated docetaxel resistance in prostate cancer and contributed to an advanced therapy combination for advanced prostate cancer patients.

Citation Format: Yixiang Li, Baotong Zhang, Jin-Tang Dong. Acetylated Kruppel-like factor 5 and transforming growth factor-β mediated drug resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-120.
Abstract LB-153: Therapeutic effect of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinaseM2 and mechanistic target of rapamycin complex 1 pathways
Authors: Kim Hyung Sik , Kim Kyeong Seok
Published: August 2019

Current clinical trials of new anticancer therapies against metastatic renal cell carcinoma (RCC), including molecular-targeted therapies, have not shown promise. The purpose of this study was to preclinically assess the antitumor effects of MC-4, a partially purified material of Artemisia annua L., as a monotherapy or in combination with the known mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, everolimus, against Caki-1 (Von Hippel-Lindau (VHL)+/+) and 786-O (VHL−/−) human RCC cells. MC-4 monotherapy significantly increased tumor growth inhibition and autophagic cell death in RCC cells in vitro and in vivo. Everolimus led to compensatory Akt activation by inhibiting only mTORC1 signaling pathway. In contrast to everolimus, MC-4 enhanced phosphatase and tensin homolog expression and reduced its downstream effector, Akt/pyruvate kinase muscle isozyme M2 (PKM2), leading to decreased expression of glucose transporter 1, which is associated with cancer cell metabolism. The synergistic antitumor and anti-metastatic effects induced by co-administration of MC-4 and everolimus involve cell growth inhibition and autophagic cell death via dual targeting of phosphatidylinositol 3-kinase (PI3K)/Akt/PKM2 and mTORC1. These findings suggest that MC-4 is a novel Akt/PKM2 inhibitor that can overcome the limitation of existing mTOR inhibitors and can be considered a novel strategy to treat patients with rapidly progressing advanced RCC.

Citation Format: Hyung Sik Kim, Kyeong Seok Kim. Therapeutic effect of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinaseM2 and mechanistic target of rapamycin complex 1 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-153.
Abstract LB-169: Comprehensive analysis of the expression of eight genes as a prognostic marker in head and neck cancer
Authors: Park Heuijoon , Zhang Yuzheng , Xu Chang , Chen Chu , Wang Pei , Méndez Eduardo
Published: August 2019

Head and neck cancer (HNC) is the 6th most common cancer worldwide, and the survival rate of HNC is about 50%. There has been no significant improvement in survival in HNC for over 50 years. Many HNC cases are not identified until an advanced stage. Thus, prevention, early detection, and better treatment are critical factors to reduce morbidity and mortality in HNC. Genome-wide next generation sequencing techniques allow investigation of patient-specific molecular signatures that may provide insight into the design of customized cancer therapies. Our previous studies have identified critical genetic signatures for HNC initiation and progression, and these signatures are strongly associated with progression-free survival (PFS) of HNC patients. To improve current molecular markers, a survival predictive model was built using ElasticNet Cox regression model with different sets of molecular markers (313 unique genes) from our three published studies and TCGA RNAseq expression data (n = 260). Deregulated expression of eight genes (FADD, PPFIA1, RYK, SMARCA2, SNX10, DCAF13, C18orf21 and THBS1) was identified and showed strong association with PFS. This eight-gene prediction model was validated by an independent oral squamous cell carcinoma (OSCC) specific mortality dataset from MD Anderson Cancer Center (n = 71 OSCC, AUC = 0.857). Next, we analyzed the association between deregulated expression of these eight genes and the top 5% (n = 420) most commonly mutated genes in HNCs (n = 260) via pairwise Pearson correlation coefficient with p value. This analysis revealed that deregulated expression of these eight genes is strongly associated with mutations in TP53 and NOTCH1. This result was confirmed by additional

analysis with a Regularized Multivariate Regression for Identifying Master Predictors (RemMap) model. Finally, to investigate the association of copy number variation (CNV) with expression of the 8-gene panel, pairwise Pearson correlation with p-value calculation was performed between the copy number data and the expression of the eight genes, and the most correlated regions were identified to be in chromosome arms 3p, 5q, and 11q. Further analysis using only HPV-negative OSCC samples revealed an association of eight-gene deregulation with CNV in 11q13.

We conclude that this new eight-gene marker panel is strongly correlated with PFS of HNC patients. Further evaluation using new HNC data sets is thus justified to establish the utility of this new eight-gene panel as a prognostic marker.

Citation Format: Heuijoon Park, Yuzheng Zhang, Chang Xu, Chu Chen, Pei Wang, Eduardo Méndez. Comprehensive analysis of the expression of eight genes as a prognostic marker in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-169.