bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4414: Inhibition of CDK2 overcomes primary and acquired resistance to CDK4/6 inhibitors
Authors: Hall Claire R. , Bisi John E. , Strum Jay C. 
Published: August 2019

Abstract
The cyclin dependent kinase (CDK) family of proteins is associated with cell cycle progression and transcriptional regulation. Abnormalities in the cell cycle, including modifications to the function of CDKs, their regulators (cyclins), or their natural inhibitors, are frequently associated with the formation and growth of tumors. While recent advances in treatments using CDK inhibition have focused on targeting CDK4/6, with regulatory approvals of palbociclib, ribociclib, and abemaciclib, these compounds only target tumors sensitive to CDK4/6 inhibitors. We are focused on developing a novel, potent, and selective inhibitor of CDK2 to treat patients whose tumors are insensitive to CDK4/6 inhibition, either by primary resistance or acquired resistance by prior treatment with a CDK4/6 inhibitor. CDK2, a serine-threonine kinase, is a member of the CDK family that binds two regulatory cyclins, E and A. CDK2 when complexed to cyclin E is involved in the G1 to S-phase transition. However, when CDK2 is complexed with cyclin A, the cell will progress through the S to M-phase. Overexpression of cyclin E has been described in a subset of triple negative breast cancer (TNBC), tumors with acquired resistance to CDK4/6 inhibition such as ER+ Her2- breast cancer, as well as ovarian, lung, and other tumor types. We have utilized medicinal chemistry and structure activity relationship (SAR) modeling, starting from our proprietary scaffold, to generate a series of small molecule CDK2 inhibitors with drug-like properties. These compounds were initially screened for potency and selectivity using an array of biochemical and in-vitro assays. We identified multiple small molecule inhibitors with sub-nanomolar biochemical IC50s for CDK2 when complexed with either cyclin E or cyclin A and evaluated their activity in normal cell lines, a breast cancer cell line resistant to CDK4/6 inhibition, TNBC, and other tumor cell lines. We examined cell cycle analysis, EdU incorporation, cell proliferation, caspase activation, and western blot analysis of genes associated with the downstream targets of CDK2. These CDK2 inhibitors potently arrest cells in the G2/M-phase and inhibit proliferation in a manner dependent on time and dose, with a corresponding decrease in phosphorylated Rb. Our lead compound was also evaluated in mouse xenograft studies for efficacy, investigating tumor growth inhibition in a model with cyclin E overexpression and a model with an acquired resistance to CDK4/6 inhibition. These potent CDK2 inhibitors demonstrate a potentially promising method of treating tumors with primary or acquired resistance to CDK4/6 inhibitors.
Citation Format: Claire R. Hall, John E. Bisi, Jay C. Strum. Inhibition of CDK2 overcomes primary and acquired resistance to CDK4/6 inhibitors [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 4414.
Abstract 4420: Small-molecule inhibition of Wee1 kinase by AZD1775 selectively sensitizes human papilloma virus (HPV)-associated cervical cancer to DNA-damaging therapies
Authors: Kobayashi Osamu , Ikeda Yuji , Okuma Yuki , Hayashi Nobuki , Nakajima Takahiro , Asai-Sato Mikiko , Kawana Kei 
Published: August 2019

Abstract
Objective: Wee1 regulate G2-M checkpoint of cell-cycle Inhibition of Wee1 promotes cell mitosis without DNA repair in cases with TP53 deficiency Since human papillomavirus (HPV) E6 involves the inactivation of p53, we aimed to evaluate effects of Wee1 inhibitor on cervical cancer.
Material and Methods: Expression level of Wee1 in cervical cancer was evaluated using Oncomine Cervical cancer cell lines, Caski (HPV16+), SiHa (HPV16+) and C33A (HPV-, P53 mut) and LNCap (HPV-, P53 wt, prostate cancer) were used. After exposure to either Wee1 inhibitor (AZD1775), cisplatin, or both, cell surviving rate was evaluated by MTT assay and expression levels of Wee1 and cell cycle related proteins were evaluated by western blotting cell cycle status in cell lines were observed by flow cytometry.
Results: High expression of Wee1 in cervical cancer was clinically observed among ten cancer species. Stepwise treatment of AZD1775 promoted significant cell death induction, compared with exposure to cisplatin alone in HPV-positive cells (Caski and Siha); however no effect on cell death in HPV-negative cells (C33A and LNCap). In addition, expression level of pCDC2 was reduced after exposure to AZD1775, indicating induction of cell mitosis without DNA repair.
Conclusion: Our results indicate the therapeutic potential of cervical cancer treatment by Wee1 inhibition. Synergistic effect of Wee1 inhibition with conventional treatments (CCRT or chemotherapy) may be a new strategy to improve the prognosis in cervical cancer.
Citation Format: Osamu Kobayashi, Yuji Ikeda, Yuki Okuma, Nobuki Hayashi, Takahiro Nakajima, Mikiko Asai-Sato, Kei Kawana. Small-molecule inhibition of Wee1 kinase by AZD1775 selectively sensitizes human papilloma virus (HPV)-associated cervical cancer to DNA-damaging therapies [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 4420.
Abstract 4421: SY-5609, an orally available selective CDK7 inhibitor demonstrates broad anti-tumor activity in vivo
Authors: Hu Shanhu , Marineau Jason , Hamman Kristin , Bradley Michael , Savinainen Anneli , Alnemy Sydney , Rajagopal Nisha , Orlando David , Chuaqui Claudio , Olson Eric 
Published: August 2019

Abstract
Previously, we reported on a series of highly potent, selective, and non-covalent CDK7 inhibitors that demonstrated antiproliferative activity against triple-negative breast cancer (TNBC) and ovarian cancer (OVA) cell lines and tumor growth inhibition in cell line-derived (CDX) and patient-derived (PDX) mouse xenograft models. Here, we report on the in vitro and in vivo profile of our development candidate, SY-5609. Methods: Kinase inhibition assays at both Km and 2 mM [ATP] were used to assess inhibition of CDK2, CDK7, CDK9, and CDK12. SPR was used to determine the Kd, kon, and koff binding characteristics of SY-5609 to immobilized CDK7/Cyclin H dimer. CDK7 compound occupancy was determined using a biotinylated small molecule probe to pull down free CDK7 following incubating of HL60 cells with SY-5609. Inhibition of tumor cell line growth was assessed following 72 hrs of incubation with SY-5609. Flow cytometry was used to assess apoptosis and cell cycle modulation after 48 hrs of treatment. Effects on DNA damage and repair were assessed by immunofluorescence staining for γH2AX and RAD51 proteins. To assess in vivo effects, mice were implanted subcutaneously and randomized for treatment when tumors reached 150-200 mm3 and dosed orally for 3 weeks by both QD and BID dosing regimens. Collected tumor tissue samples were analyzed for protein levels of MCL1, pCDK2, MYC, and RNA Pol II CTD pSer5 by western blot. Results: SY-5609 bound CDK7/Cyclin H with a Kd of 0.059 nM and occupied CDK7 in HL60 cells with an EC50 of 33 nM. Cell growth inhibition EC50 values were 6-17 nM in a panel of solid tumor cell lines. Selectivity of SY-5609 over CDK12, CDK9, and CDK2 was 2492-, 2508-, and 8068-fold, respectively. SY-5609 led to induction of apoptosis, cell cycle arrest, and inhibition of DNA damage repair in tumor cell lines. Dose-dependent tumor growth inhibition was observed in a panel of CDX and PDX solid tumor models with both QD and BID dosing of SY-5609 with resulting decreases in direct (pCDK2, RNA Pol II CTD pSer5) and indirect (MCL1, MYC) protein biomarkers. In summary, we describe SY-5609, an orally available, potent, and selective CDK7 inhibitor that drives strong responses in CDX and PDX tumor models. These data support the rationale for advancing SY-5609 into IND-enabling studies.
Citation Format: Shanhu Hu, Jason Marineau, Kristin Hamman, Michael Bradley, Anneli Savinainen, Sydney Alnemy, Nisha Rajagopal, David Orlando, Claudio Chuaqui, Eric Olson. SY-5609, an orally available selective CDK7 inhibitor demonstrates broad anti-tumor activity in vivo [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 4421.
Abstract 4422: Molecular and functional characterization of alpha satellite non-coding RNAs
Authors: Cáceres Rodrigo E. , Andonegui Marco A. , Oliva Diego A. , González Rodrigo , Luna Fernando , Arriaga Cristian G. , López Alejandro , Prada Diddier G. , Castro Clementina , Molina Paulina , Rosa Carlos De la , Reyes José L. , Hédouin Sabrine , Hubé Florent , Francastel Claire , Herrera Luis A. 
Published: August 2019

Abstract
Eukaryotic cell cycle progression requires the coordination of multiple molecular events in space and time to bring about proper transition from one phase to the next, and to ensure faithful genomic inheritance to daughter cells. The roles of coding transcription, translation, and RNA/protein degradation in cell cycle regulation are straightforward, since they control the abundance of proteins necessary for its progression. However, the contribution of non-coding transcription to this process is poorly understood. Non-coding transcription is notoriously interesting in mitosis for two reasons: First, transcription is repressed in most of the genome, but it is active in the centromere itself during mitosis; second, centromeric transcription produces non-coding RNA molecules which are integral components of the centromere and kinetochore and have functional roles in chromosome segregation. Here, we characterized the centromeric human alpha satellite non-coding RNAs (cencRNAs). We detected that the centromere produces high-molecular-weight (&gt5 kb) alpha satellite transcripts in sense and antisense orientation in several cancer cell lines and normal human leukocytes. These RNAs have a half-life of ~ 30 min and vary in abundance, but not in size, throughout the cell cycle. By analyzing their abundance under various conditions that promote mitotic arrest, we discovered a new association between proteasome inhibition and cencRNAs overexpression in G2/M HCT116 cells. We also show that their transcriptional inhibition mitigates the mitotic arrest induced by proteasome inhibitors. Furthermore, we demonstrate that exogenous expression of cencRNAs can slightly increase the mitotic index of SW480 cells. Using mass spectrometry-coupled RNA pulldown, we discovered that these RNAs interact with proteins essential for chromosome segregation. Our data show that centromeric transcription is regulated by proteasomes. Proteasomal inhibition promotes abnormal mitotic progression owing to the overexpression of non-coding RNAs at the onset of mitosis and the presumed impairment of their partner proteins functions in mitosis.
Citation Format: Rodrigo E. Cáceres, Marco A. Andonegui, Diego A. Oliva, Rodrigo González, Fernando Luna, Cristian G. Arriaga, Alejandro López, Diddier G. Prada, Clementina Castro, Paulina Molina, Carlos De la Rosa, José L. Reyes, Sabrine Hédouin, Florent Hubé, Claire Francastel, Luis A. Herrera. Molecular and functional characterization of alpha satellite non-coding RNAs [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 4422.
Abstract 4426: Selective inhibition of CDK9 induces apoptosis of TNBC cells independent of Rb status
Authors: Brighton Hailey E. , Hall Claire R. , Dillon Kerry A. , Bisi John E. , Strum Jay C. 
Published: August 2019

Abstract
The family of cyclin-dependent kinases (CDKs) are serine/threonine protein kinases important for cell cycle control and/or regulation of transcription. CDK9/CyclinT1 is a key regulator of transcription in eukaryotic cells and has been shown to be dysregulated at the level of protein and kinase activity in both hematologic and solid tumors. CDK9/CyclinT1 forms the active P-TEFb complex and phosphorylates Ser2 residues in the carboxy-terminal domain of RNA polymerase II (RNApol II) to initiate elongation of mRNA transcripts. CDK9 activity regulates transcription of a variety of short-lived transcripts that promote survival and directly suppress apoptosis in cancer cells, including MYC,XRN2, MCL-1,and XIAP. MYC-driven tumor types with Rb-loss or high expression levels of cyclin E, such as triple negative breast cancer (TNBC), are difficult to treat and are resistant to existing CDK4/6 inhibitors. Since CDK9 is upstream of these oncogenic drivers, inhibition of CDK9 could potentially bypass innate resistance mechanisms and induce cell death in TNBC through blocking expression of MYC and MCL-1, for example. To target CDK9 in TNBC, we used structure-based drug design and developed a library of novel, potent and selective CDK9 inhibitors (CDK9i). The lead CDK9i exhibit single digit nanomolar potency against CDK9/CyclinT1 complexes and good selectivity against other CDK family members in biochemical assays.
In addition, they also display high selectivity over 502 other kinases. Lead CDK9 inhibitors were found to potently inhibit phosphorylation of RNApol II Ser2 in a time and dose dependent manner in TNBC cells and decrease MYC, MCL-1 and XIAP at both mRNA and protein levels. Additionally, treatment of TNBC cells led to a potent G2/M cell cycle arrest, inhibition of cell proliferation and induction of apoptosis within 24 hours, regardless of Rb status of the tumor cells. Primary human bone marrow and normal human fibroblast cells, however, did not undergo apoptosis within 72 hours of treatment with CDK9i, suggesting a potential therapeutic window for CDK9i treatment. Further studies are ongoing to assess the effect of dose and scheduling on tumor efficacy in mouse TNBC tumor models. Selective inhibition of CDK9 presents a novel treatment strategy for difficult-to-treat tumor types, including those resistant to existing targeted therapeutics.
Citation Format: Hailey E. Brighton, Claire R. Hall, Kerry A. Dillon, John E. Bisi, Jay C. Strum. Selective inhibition of CDK9 induces apoptosis of TNBC cells independent of Rb status [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 4426.
Abstract 4427: LS007, a potent and orally bioavailable CDK9 inhibitor, suppresses the growth of triple-negative and estrogen receptor-positive breast cancer
Authors: Rahaman Muhammed Hamidur , Zhang Yinghui , Islam Md Saiful , Heinemann Gary , Anshabo Abel Tesfaye , Albrecht Hugo , Milne Robert , Wang Shudong 
Published: August 2019

Abstract
Treatment of breast cancer represents a major therapeutic challenge, and thus identification of new targeted therapy is of paramount importance. Anti-apoptotic proteins, BCL2 and MCL1, and oncoprotein c-MYC are implicated in evasion of apoptosis and resistance to chemotherapy in both triple-negative breast cancer (TNBC) and estrogen receptor-positive breast cancer (ER+ BC). Transcription of these oncogenic factors requires cyclin dependent kinase 9 (CDK9). CDK9 phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAPII) and acts as a rate-limiting step of transcription. Thus, targeting CDK9 can reduce the expression of these proteins effectively and simultaneously, presenting a promising therapeutic strategy for breast cancer. Utilizing extensive medicinal chemistry and biochemical assays, we previously identified and developed LS007 as an orally bioavailable (F = 56% in cynomolgus monkey at 4 mg/kg), and nanomolar inhibitor of CDK9 (Ki = 4 nM). In vitro, inhibition of CDK9-mediated phosphorylation of RNAPII (pRNAPIIS2) by LS007 resulted in downregulation of BCL2, MCL1 and c-MYC and activation of PARP cleavage indicating apoptosis in breast cancer cells (TNBC: MDA-MB-231, Hs578T and ER+ BC: MCF-7, T47D). In vivo, LS007 was well tolerated in mice after oral administration (MTD = 50 mg/kg QD and 100 mg/kg Q3D). In MDA-MB-231 TNBC xenograft, by daily oral dosing at 25 mg/kg and 50 mg/kg LS007 significantly reduced tumor growth (p &lt; 0.001) with T/C of 53 % and 35 %, respectively, on day 21, when compared to the vehicle dosed group. Similarly, in MCF-7 ER+ BC xenograft model, oral dosing of LS007 at 25 mg/kg QD, 50 mg/kg Q2D and 75 mg/kg Q3D showed significant tumor growth inhibition with T/C of 50 %, 60 % and 47 %, respectively, and increased in animal survival (p &lt; 0.001) compared to vehicle control. It was safe in the xenograft models as there was no significant body weight loss or other overt toxicities. In addition, histological analysis of major organs (liver, kidney, heart, bone marrow and intestine) of the mice receiving LS007 showed no drug related toxicities. These results support for development of LS007 towards the clinical trials for the treatment of TNBC and ER+ BC.
Citation Format: Muhammed Hamidur Rahaman, Yinghui Zhang, Md Saiful Islam, Gary Heinemann, Abel Tesfaye Anshabo, Hugo Albrecht, Robert Milne, Shudong Wang. LS007, a potent and orally bioavailable CDK9 inhibitor, suppresses the growth of triple-negative and estrogen receptor-positive breast 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 4427.
Abstract 4429: Delivery of miR-143 and miR-506 with novel nano carrier to arrest cell cycle in lung cancer
Authors: Hossian A K M Nawshad , Muthumula Chandra Mohan Reddy , Mattheolabakis George 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer related deaths worldwide. Although targeting the cell cycle of cancer cells has been a promising approach, no such therapy has translated for the treatment of lung cancer. In our previous work, we identified that the combinatorial treatment of two miRNAs, miR-143 and miR-506, inhibited the cell cycle of lung cancer cells in vitro. These miRs downregulated the CDK1 and CDK4/6 genes, which are involved in the G1/S and G2/M transitions, respectively. Nucleic acid delivery has met formidable challenges, such as short in vivo half-life and rapid degradation in the circulation, as well as limited cell penetration or endosomal escape. We developed a novel nanocarrier, composed of tocopherol (vitamin E), polyethylenenimine, and polyethylene glycol (TPP) in 1:1:1 molar ratio for the delivery of miRNAs. Proper characterization with NMR and FTIR confirmed the synthesis of this molecule. We found it can form nanomicelles, and the positively charged of polyethyleneimine allowed for the complexation of miRNAs, as was detected by a gel retardation assay. Fluorescently tagged TPP micelles were uptaken by cancer cells, and the carrier successfully transfected cancer cells with the combinatorial miRNA treatment inducing gene downregulation. In vivo pharmacokinetics study using a subcutaneous mouse model of lung cancer indicated prolonged accumulation of the TPP-miRNA micelles in the tumor area. In vivo administration of the miR-143/506 in TPP micelles, along with cisplatin co-treatment, inhibited tumor growth in a subcutaneous mouse model of lung cancer. Overall, the promising role of miR-143 and 506 for
the regulation of LC growth may be achieved by this novel TPP-based nanocarrier, which merits further evaluation.
Citation Format: A K M Nawshad Hossian, Chandra Mohan Reddy Muthumula, George Mattheolabakis. Delivery of miR-143 and miR-506 with novel nano carrier to arrest cell cycle in lung 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 4429.
Abstract 4430: Simulating delivery of TTFields to the infratentorium in patients with brainstem gliomas
Authors: Ramirez-Fort Marigdalia K. , Cross Brittany , Naveh Ariel , McClelland Shearwood , Mendez Melissa , Santiago Roberto , Mahase Sean S. , Matta Jaime , Bomzon Ze'ev , Lange Christopher S. 
Published: August 2019

Abstract
Purpose/Objective(s): TTFields are FDA-approved for the treatment of recurrent and newly diagnosed Glioblastoma (GBM) in the supratentorial brain. The EF-14 trial showed that combining TTFields with adjuvant chemo-radiation leads to a significant increase in overall survival compared to adjuvant chemo-radiation alone. High-grade gliomas also occur in the infratentorium and brainstem of pediatric and adult patients. Brainstem gliomas have a median survival of 9 to 11 months, necessitating the exploration of novel treatment combinations, such as delivering TTFields to the infratentorial brain.
We recently showed in a simulation-based study that TTFields can be successfully delivered to the infratentorium. Effective delivery was achieved by placement of the arrays on the vertex, bilateral posterolateral occiput, and superior-posterior neck; the array placement results in TTFields at therapeutic intensities throughout the brainstem and cerebellum of realistic computational head models.
The previous simulation-based study was performed using realistic computational models of healthy individuals; it did not provide detailed insight into field distributions within tumor tissue located in the infratentorium. Here, we aim to expand the results of this previous study, by simulating the delivery of TTFields to the infratentorium of adult and pediatric patients with high-grade brainstem gliomas.
Materials/Methods: A realistic computational model was created using MRI data of adult and pediatric patients with high-grade brainstem gliomas. Transducer arrays were placed on the model and the delivery of TTFields to the infratentorial brain was then simulated using a commercial numerical solver. The electric field distribution in the supratentorium, infratentorium, and within the tumor were derived from the simulations, and the dose in the tumor analyzed.
Results: The distribution of calculated isofield lines demonstrates effective delivery of TTFields to infratentorial brain tumors.
Conclusion: Our results provides rationale for clinically investigating the utility of TTFields in treating infratentorial high-grade gliomas.
Citation Format: Marigdalia K. Ramirez-Fort, Brittany Cross, Ariel Naveh, Shearwood McClelland III, Melissa Mendez, Roberto Santiago, Sean S. Mahase, Jaime Matta, Ze'ev Bomzon, Christopher S. Lange. Simulating delivery of TTFields to the infratentorium in patients with brainstem gliomas [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 4430.