bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1313: TH1902, a docetaxel peptide-drug conjugate, shows pre-clinical efficacy in several Sortilin-positive (SORT1+) cancers
Authors: Marsolais Christian , Currie Jean-Christophe , Demeule Michel , Charfi Cyndia , Larocque Alain , Zgheib Alain , Béliveau Richard , Annabi Borhane 
Published: July 2021

Abstract
One strategy to achieve greater selectivity of anticancer drug to cancer cells is the conjugation of cytotoxic agents to peptide ligands that selectively target receptors abundantly expressed in these tumor cells. Recently, increased expression of sortilin (SORT1), a scavenging receptor, has been observed in various cancers including breast, ovarian, endometrial, skin, colorectal and pancreatic cancers. In light of these SORT1 levels, we developed a peptide conjugation platform to target SORT1 and to increase cell selectivity and internalization of anticancer agents. Docetaxel was conjugated to a sortilin-binding proprietary peptide (TH19P01). High in vitro intracellular internalization of TH19P01 in TNBC cells was first confirmed and was reduced when SORT1 expression was silenced using siRNA or upon competition with the SORT1 ligands neurotensin and progranulin. Significant in vitro intracellular delivery of the docetaxel-TH19P01 conjugate (TH1902) was observed in SORT1+ cancer cell lines while maintaining efficient docetaxel cytotoxic mechanism. TH1902 further exerted potent anti-proliferative and anti-migratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 also triggered faster and more potent apoptotic cell death than did docetaxel. Pre-clinical in vivo studies were performed in human SORT1+ tumor xenografts grown in mice including TNBC (MDA-MB-231 and HCC-70), melanoma (SK-MEL-28), colorectal (HT-29) and pancreatic (PANC-1) cancer models. Mice were treated with either TH1902 or docetaxel by IV bolus injections at equivalent doses of docetaxel (MTD or ¼ MTD). In all cases, TH1902 showed more potent inhibition than Docetaxel. These results strongly support future clinical development of TH1902 as novel therapeutics in SORT1+ cancers.
Citation Format: Christian Marsolais, Jean-Christophe Currie, Michel Demeule, Cyndia Charfi, Alain Larocque, Alain Zgheib, Richard Béliveau, Borhane Annabi. TH1902, a docetaxel peptide-drug conjugate, shows pre-clinical efficacy in several Sortilin-positive (SORT1+) cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1313.
Abstract 1318: Mechanochemical dynamic therapy for focal cancer treatment
Authors: Kim Gun , Wu Qiong , Chu James L. , Smith Emily J. , Oelze Michael L. , Li King C. , Moore Jeffrey S. 
Published: July 2021

Abstract
This study proposes a new cancer drug delivery modality that allows for spatiotemporal control over activation of the therapeutic. Current standard cancer therapies of surgery, chemotherapy, and radiation therapy have their limitations, such as invasiveness and systemic toxicities. Developing a new modality that is localized and triggerable is becoming increasingly advantageous. Currently, photodynamic therapy (PDT) has been shown to be clinically effective but is limited by poor tissue penetration of light. Sonodynamic therapy (SDT) bypasses this pitfall with increased tissue penetration depth of ultrasound. However, PDT has limitations as it relies on the potentially damaging ultrasound cavitation effect and requires sonosensitizers or nanoparticles that have issues with bioavailability, biostability, and biosafety. In this study, we propose a novel ultrasound-based cancer treatment modality called mechanochemical dynamic therapy (MDT). In MDT, high intensity focused ultrasound (HIFU) delivers mechanical forces to force-responsive moieties of azo mechanophores that are embedded into biocompatible polyethylene glycol (PEG) hydrogel polymers. Upon focal sonication with HIFU, these mechanophores generate highly reactive free radicals (FRs) that are converted to reactive oxygen species (ROSs). The sonicated gels are then placed into in vitro cultures, allowing for the diffusion of ROSs into the cells to induce oxidative cytotoxicity and eventually cell death. Cell proliferation is monitored at 24-hour intervals, and by 72 hours, the sonicated gels produced cell killing effects comparable to lethal doses of H2O2 in both in vitro mouse melanoma (B16F10) and breast cancer (E0771) models. Sonication of control hydrogels that did not contain mechanophores showed minimal cytotoxicity. This study shows the potential of MDT as a drug delivery platform that overcomes the limitations of PDT and SDT and has the potential to be applied synergistically with other current cancer treatments. This is the first demonstration of using HIFU-activated mechanophores to non-invasively deliver cancer therapies with spatiotemporal control.
Citation Format: Gun Kim, Qiong Wu, James L. Chu, Emily J. Smith, Michael L. Oelze, King C. Li, Jeffrey S. Moore. Mechanochemical dynamic therapy for focal cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1318.
Abstract 1319: Rapid accumulation of cytotoxic payload in tumor tissue drives BT5528 activity in tumor models
Authors: Lahdenranta Johanna , Bennett Gavin , Huxley Philip , Mudd Gemma , Upadhyaya Punit , Jeffrey Phil , Keen Nicholas 
Published: July 2021

Abstract
BT5528 was developed as a Bicycle® toxin conjugate to deliver monomethyl auristatin E (MMAE) -payload to EphA2 overexpressing tumors. It consists of a bicyclic peptide targeting the tumor antigen EphA2, linked to the cytotoxin MMAE via a molecular spacer and cleavable linker. Administration of BT5528 results in rapid uptake of payload into EphA2 overexpressing xenograft tumors associated with persistent toxin levels in tumor tissue and limited systemic exposure of both parent drug and payload (1). BT5528 showed a favorable preclinical profile supporting the initiation of a first-in-human Phase I/II study (NCT04180371) to investigate safety and efficacy of BT5528 in indications with evidence of EphA2 expression including non-small-cell lung cancer (NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), gastric/upper gastrointestinal (GI), pancreatic and urothelial cancers (2). We have used EphA2 overexpressing tumor xenograft models in both mice and rats to elucidate the relative differences between toxin payload delivery and systemic exposure of BT5528. Comparison of payload-delivery and systemic exposure from EphA2 -targeted Bicycle toxin conjugate and antibody-drug conjugate (ADC) demonstrate the differentiation of these toxin-payload delivery platforms. ADC payload delivery depends upon a sustained plateau-like pharmacokinetic (PK) profile that exposes target and potentially nontarget organs to intact ADC for several days. In contrast, BT5528 achieves prolonged toxin delivery to tumors, following transient exposure in plasma of less than one hour. A Phase I/II study of BT5528 in patients with solid tumors is ongoing, which will investigate if this PK novel, differentiated pharmacokinetic profile, unique to Bicycle toxin conjugates, gives rise to a favorable balance of efficacy and safety. References: 1. Bennett et al. Mol. Cancer Ther. 2020;19:1385-942. 2. Bendell et al. TPS3655 Journal of Clinical Oncology 38, no. 15_suppl
Citation Format: Johanna Lahdenranta, Gavin Bennett, Philip Huxley, Gemma Mudd, Punit Upadhyaya, Phil Jeffrey, Nicholas Keen. Rapid accumulation of cytotoxic payload in tumor tissue drives BT5528 activity in tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1319.
Abstract 1322: Evaluating intracellular accumulation profiles of chemotherapeutic agents using CLENs for the treatment of Y79 retinoblastoma
Authors: Luo Nan , Patel Virali , Patel Minesh , Conte Eric , Campbell Robert 
Published: July 2021

Abstract
Retinoblastoma is the most common intraocular malignancy in children, with approximately 200-300 new cases in the United States each year. Currently, conventional chemotherapy agents (carboplatin, cisplatin, doxorubicin, vincristine, and cyclophosphamide) used to treat retinoblastoma, are rapidly eliminated from circulation. Novel lipid nanoparticles (LNP) have been shown to improve delivery of encapsulated chemotherapeutic agents to Y79 retinoblastoma cells, and therefore the agents are less toxic to healthy cells. Past studies have supported the use of LNP delivery systems to enhance chemotherapeutic drug action against Y79 retinoblastoma cells as well. The experimental plan will now evaluate the use of cellular membrane lipid-extracted nanoliposomes (CLENs) to examine targeting using cellular models of retinoblastoma. Y79 cells were cultured in RPMI growth medium supplemented by 20% FBS. CLENs and lipid extracts (LE) were prepared according to previously published protocols. Following the development of Y79-LE nano-preparations consisting of DOPC, Y79-LE, and cholesterol at different ratios, preparations were evaluated in terms of physicochemical properties and uptake by Y79 cells. The additional inclusion of cationic lipid DOTAP in Y79-LE preparations was evaluated for select preparations. Particle sizes and zeta potential values were determined for each preparation type by ZetaPALS. CLENs exhibited an average particle size between 400 to 600 nm. Experiments with Y79-CLENs prepared in the absence and presence of DOTAP, showed they were taken up by the target cell population. In general, the inclusion of Y79-LE increased cellular uptake. The inclusion of cholesterol in combination with DOTAP showed enhanced liposomal uptake in Y79 retinoblastoma cells. Evidence from previous studies suggest a benefit of using lipid nanoparticles compared to more conventional treatment options. Preliminary findings suggest a positive correlation between the particle size and degree of cellular uptake. Additional optimization studies are currently underway.
Citation Format: Nan Luo, Virali Patel, Minesh Patel, Eric Conte, Robert Campbell. Evaluating intracellular accumulation profiles of chemotherapeutic agents using CLENs for the treatment of Y79 retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1322.
Abstract 1323: Novel autophagy inhibitor to treat pancreatic cancer
Authors: Ramachandran Mythili , Ma Zhao , Li Yuanpei 
Published: July 2021

Abstract
In this study, we develop a novel autophagy inhibitor targeting one of the most aggressive cell populations present in pancreatic tumors, the pancreatic cancer stem cell (CSC). Targeting this population which has the malignant properties of tumorigenesis/tumor recurrence, the ability to differentiate into a heterogenous tumor cell types and can self-renew is a new strategy to alleviate the current dismal 10% five-year survival rate of pancreatic cancer. Here we characterize an autophagy inhibitor which is a first-in-class nanoparticle comprised of a chloroquine-derived small molecule drug that can self-assemble into a micelle. Due to its favorable pharmacokinetic properties and the CSC reliance on autophagy, our compound is able to selectively target this cell population both in vitro and in vivo. Additionally, the compound has shown synergy with the current standard of care chemotherapeutic, gemcitabine, with an 88.9% reduction in tumor volume in the combination of the two drugs compared to gemcitabine treated alone (p&lt;0.0001) in two separate treatment regimens using a pancreatic PDX mouse model. We further illustrate that the stem cell population is targeted by inhibiting tumorsphere formation in established pancreatic cancer cell lines MIA-PaCa2 and PANC-1 and in pancreatic PDX-derived CSCs in vitro. The drug treatment also promotes a decrease in pluripotency markers, particularly in Sox2 levels. Finally, the drug is well-tolerated with a maximum tolerated dose above 100 mg/kg in mice and is orally bioavailable.
Citation Format: Mythili Ramachandran, Zhao Ma, Yuanpei Li. Novel autophagy inhibitor to treat pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1323.
Abstract 1324: Evaluation of KIF14 in a chemotherapeutic resistant breast cancer cell line
Authors: Cleghorn Keeley , Steding Catherine E. 
Published: July 2021

Abstract
The purpose of this study is to elucidate the mechanisms of KIF14 in acquired paclitaxel chemoresistance in a breast cancer cell line by evaluating its expression, activity, and regulatory network. Chemoresistance remains the single greatest cause of therapeutic failure in cancer therapeutics. Development of chemoresistance for compounds that often only suppress growth and do not eliminate tumors has been shown to correlate with more severe clinical phenotypes. Paclitaxel, the microtubule stabilizing compound, has been shown to be of particular importance in the study of chemoresistance as its therapeutic efficacy has been directly shown to be tempered by resistance. Whole transcriptome analysis of long-term chemoresistant breast cancer cells generated at Indiana State University identified a gene not previously reported to play a role in the acquired chemoresistance of breast cancer, kinesin family member 14, KIF14 (Table 1). A knockdown of KIF14 in a chemoresistant breast cancer cell line was performed using Lipofectamine™ 3000 Transfection Reagent. Western Analysis and RT- PCR was performed to confirm the expression of the gene both before and after knockdown was performed. Once expression alterations were confirmed, a proliferation assay, population doubling assay, and a colony formation assay were performed to explore the effects of the gene knockdown in response to paclitaxel treatment. Findings from these studies identify a potential role for KIF14 and microtubule dynamics in acquired chemoresistance against paclitaxel.
KIF14 sequencing analysis performed using Illumina HiSeq4000 technology in chemoresistant cellsGeneLog2 Fold Change in Resistant CellsP-valueFDRKIF141.592.83x10-154.18x10-14
Citation Format: Keeley Cleghorn, Catherine E. Steding. Evaluation of KIF14 in a chemotherapeutic resistant breast cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1324.
Abstract 1327: Role of intra-tumoral bacteria in EGFR-tyrosine kinase inhibitor resistance
Authors: Li Wendong , Rotter-Maskowitz Aviva , Sun Ting , Zhang Keqiang , Straussman Ravid , Raz Dan 
Published: July 2021

Abstract
Mutations of the epidermal growth factor receptor (EGFR) are the most common group of actionable mutations in lung cancer, and they predict response to EGFR-tyrosine kinase inhibitos (EGFR-TKIs). The third-generation EGFR-TKI osimertinib is the standard of care for first-line treatment of patients with advanced EGFR-mutated lung cancer. Although most lung cancers with EGFR-mutation respond to osimertinib, resistance is eventually observed in all patients, and there are no approved targeted therapies once resistance to osimertinib occurs. Mechanisms of resistance to osimertinib are poorly understood and involve both EGFR and non-EGFR related pathways. Intra-tumoral bacteria are emerging as a cause of therapy resistance in cancer.Intra-tumoral bacteria have been reported in many cancers and emerging evidence suggests that the tumor microbiome plays an important role in drug resistance in a variety of cancers. But the link between intra-tumoral bacteria and therapy resistance in lung cancer remains elusive. We previously described the tumor microbiome identified within a cohort of non-small cell lung cancers. In order to determine if intra-tumoral bacteria within lung adenocarcinoma patient with EGFR mutation could play role on the resistance to EGFR-TKIs, such as osimertinib and erlotinib, we used a bacterial pre-conditioned medium (PCM) screening system which utilized various bacteria identified in lung cancer specimens. We used a cell viability evaluation method in GFP-labeled PC9 cells (EGFR Ex19del) to identify the bacterial PCM that may lead to resistance to EGFR-TKIs. We found that PCM from Chryseobacterium indologenes (C-PCM) markedly rescued PC9 cells from osimertinib or erlotinib treatment. We also found that proteinase K treatment eliminated the rescue of C-PCM on EGFR-TKI treatment, suggesting that a proteins within C-PCM are responsible for its effect of EGFR-TKI treatment. Mass spectrometry (MS) analysis showed that C-PCM does not degrade osimertinib or erlotinib, suggesting that C-PCM mediated resistance does not occur through drug degradation. Western blot analysis showed that C-PCM does not affect EGFR, phospho-EGFR, or AKT expression level but C-PCM significantly increased AKT phosphorylation level. Our current studies indicated that intra-tumoral bacteria within lung adenocarcinoma patient may leads to resistance to osimertinib and erlotinib. Further mechanistic studies of C-PCM mediated resistance are under way and may lead to new therapies to overcome osimertinib-resistance.
Citation Format: Wendong Li, Aviva Rotter-Maskowitz, Ting Sun, Keqiang Zhang, Ravid Straussman, Dan Raz. Role of intra-tumoral bacteria in EGFR-tyrosine kinase inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1327.
Abstract 1348: Targeted degradation of PARP14 Using a heterobifunctional small molecule
Authors: Wigle Tim , Ren Yue , Molina Jennifer , Blackwell Danielle , Schenkel Laurie , Swinger Kerren , Cheug Anne , Abo Ryan , Minissale Elena , Lu Alvin , Majer Christina , Church William , Dorsey Bryan , Niepel Mario , Perl Nicholas , Kuplast-Barr Kristy , McEachern Kristen , Vasbinder Melissa , Keilhack Heike , Kuntz Kevin 
Published: July 2021

Abstract
PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types and has been shown to promote the pro-tumor M2 polarization of macrophages and support Th2/Th17 signaling in models of allergic airway disease. PARP14 is a large 203 kDa protein that possesses a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrates, three macrodomains that bind mono-ADP-ribose, a WWE domain that serves as a binding module for poly-ADP-ribose, and an RNA recognition motif. We have previously shown that the potent and reversible enzymatic inhibitor, RBN012759 (IC50 &lt; 0.003 μM, 300-fold selective over monoPARPs, &gt; 1,000-fold selective over polyPARPs), links PARP14 catalytic inhibition with suppression of the antitumor immune response in human primary macrophages and human kidney cancer explants. While this catalytic inhibitor of PARP14 was able to suppress IL-4-driven pro-tumor gene expression in macrophages, it is unknown what roles the non-enzymatic biomolecular recognition motifs play in the biological function of PARP14. To further understand this, we describe a heterobifunctional small molecule, RBN012811, based on a catalytic inhibitor of PARP14 that binds in the enzyme's NAD+-binding site and recruits the E3 ligase cereblon to ubiquitinate PARP14 and selectively target it for degradation. RBN012811 has a IC50 of 0.01 μM against PARP14 in a biophysical assay and is at least 200-fold selective over all other PARPs. In KYSE-270 cancer cells, RBN012811 has a half-maximal degradation concentration (DC50) of 0.005 μM and it does not cause degradation of other PARP enzymes. In human primary macrophages PARP14 degradation by RBN012811 led to a dose-dependent decrease of IL-10 release induced by IL-4 stimulation. Our data demonstrates that RBN012811 is a useful tool to enable further exploration of the role of PARP14 in inflammation and cancer.
Citation Format: Tim Wigle, Yue Ren, Jennifer Molina, Danielle Blackwell, Laurie Schenkel, Kerren Swinger, Anne Cheug, Ryan Abo, Elena Minissale, Alvin Lu, Christina Majer, William Church, Bryan Dorsey, Mario Niepel, Nicholas Perl, Kristy Kuplast-Barr, Kristen McEachern, Melissa Vasbinder, Heike Keilhack, Kevin Kuntz. Targeted degradation of PARP14 Using a heterobifunctional small molecule [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1348.
Abstract 1368: Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors
Authors: Mehta Krina , Koshiba Shoko , Hasegawa Maki , Tayama Tomonori , Marsteller Douglas , Fox Floyd , Liu Yi , Efuni Sergey , Healy Denis , Hruska Matthew 
Published: July 2021

Abstract
BACKGROUND: KHK2455 is an oral selective inhibitor of Indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an active immunotherapy to treat advanced or metastatic solid tumors. IDO1 is a rate-limiting enzyme that converts tryptophan (TRP) to kynurenine (KYN) and is linked to immunosuppression. IDO1 inhibition results in immune modulatory effects which may be important in boosting anti-cancer immune responses. The goal of this analysis was to develop a population pharmacokinetics (PK)-pharmacodynamics (PD) model to characterize KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors.
METHOD: Plasma KHK2455 concentration, plasma KYN and TRP concentration were obtained from 36 subjects with locally advanced or metastatic solid tumors who received KHK2455 at 0.3, 1, 3, 10, 30, or 100 mg QD as a monotherapy run-in followed by combination therapy with anti-CCR4 antibody mogamulizumab in this first in human study of KHK2455. The nonlinear mixed effects modeling approach was used to develop a population PK-PD model using the data from both mono- and combination-therapy. The ratio of KYN to TRP (K:T ratio) was used as a PD marker.
RESULTS: The population PK model included one-compartment model with transit compartment absorption, enterohepatic cycling, and linear elimination. The K:T ratio was well described by an indirect response model. Steady state simulations showed that, when compared to baseline, the K:T ratio decreased with increasing KHK2455 dose and reached to a constant nadir at 100 mg dose.
CONCLUSIONS: A population PK-PD model was established to characterize the KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. The PK-PD model will enable dose optimization simulations for the planned studies.
ACKNOWLEDGEMENTS: We would like to express special appreciation to Dr. Solmaz Sahebjam, MD, for help in publishing this abstract.
Citation Format: Krina Mehta, Shoko Koshiba, Maki Hasegawa, Tomonori Tayama, Douglas Marsteller, Floyd Fox, Yi Liu, Sergey Efuni, Denis Healy, Matthew Hruska. Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1368.