bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4940: Proteasome and survivin inhibitors synergize to inhibit the growth of oral cancer organoids
Authors: Furqan Muhammad , Aleem Iffat , Tahseen Muhammad , Hussain Raza , Loya Asif , Mahmood Muhammad Tariq , Gautier Philippe , Myant Kevin , Saleem Saira , Faisal Amir 
Published: April 2023

Abstract
Oral squamous cell carcinoma (OSCC) is the most prevalent subtype of head and neck cancers that has a disproportionately high incidence and mortality in developing countries in South-Central Asia, including Pakistan. The standard treatment for OSCC generally consists of surgery combined with radiotherapy or chemotherapy; however, the overall survival rates have not improved, and only ~50% of patients survive the disease. Therefore, identifying and validating new drug targets can provide new therapeutic options for improved treatment and better prognosis for OSCC patients. The present study aimed to develop an organoid model from patient-isolated primary tumour cells and determine their drug sensitivity profile coupled with mutational analysis. New combinations of targeted drugs with synergistic activity in oral cancer cells were identified through high-throughput screening followed by validation of their activity in oral cancer cells in 2D monolayer and 3D organoid cultures. Results indicate a synergistic activity of proteasome (PR-171) and survivin (YM155) inhibitors in all tested patient-derived tumour cells and four oral cancer cell lines. Moreover, chitosan-based nanocapsules harboring these drugs showed therapeutic efficacy comparable to free drug combinations, indicating a potential for efficient and targeted delivery. Next-generation sequencing data identified missense mutations in eleven cancer-related genes that encode BRAF, EGFR, KRAS, NRAS, HRAS, MEK1, PIK3CA, PTEN, NOTCH1, TP53 and TERT. The ongoing research aims to correlate the drug sensitivity data with the mutational profile of patient-derived tumour cells to find novel targets. In conclusion, we have developed 3D organoids from patient-derived primary tumours and utilized them to validate the synergistic combination between screen-identified proteasome and survivin inhibitors. Our preclinical study provides a rationale for further evaluation of the novel drug combination in vivo and in clinical settings.
Citation Format: Muhammad Furqan, Iffat Aleem, Muhammad Tahseen, Raza Hussain, Asif Loya, Muhammad Tariq Mahmood, Philippe Gautier, Kevin Myant, Saira Saleem, Amir Faisal. Proteasome and survivin inhibitors synergize to inhibit the growth of oral cancer organoids. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4940.
Abstract 4943: SP-1-39 as a novel tubulin inhibitor overcomes taxane resistance in castration-resistant prostate cancer model
Authors: Wang Rui , Hartman Kelli L. , Pochampally Satyanarayana , Miller Duane D. , Li Wei 
Published: April 2023

Abstract
Colchicine binding site inhibitors have proven to have potent anti-cancer efficacy in many cancer types. Inhibition of tubulin polymerization, a popular mechanism of action for anti-cancer activities, will be activated once the inhibitor interacts with the colchicine binding site. We have previously developed and reported a potent tubulin inhibitor (SB-216). One of its derivatives, the compound SP-1-39, a pyrimidine dihydroquinoxalinone derivative, has been recently designed to further improve the potency and therapeutic properties. Here, we examined the impact of SP-1-39 on preclinical prostate cancer models in vitro and in vivo. EBI competition assay confirmed that SP-1-39 binds to colchicine-binding site and inhibits the formation of EBI:β-tubulin adduct. The anti-proliferation abilities of SP-1-39 was tested against melanoma, breast cancer, pancreatic cancer, prostate cancer, and paclitaxel-resistant prostate cancer cell lines by MTS assay, and defined IC50 values of 0.2-4 nmol/L. Other in vitro results showed SP-1-39 disrupted microtubule network, induced cell cycle arrest at G2/M phase, and caused apoptosis in paclitaxel-resistant human prostate cancer cells (PC-3/TxR). For in vivo study, 2.5mg/kg SP-1-39 significantly attenuated tumor growth in PC-3/TxR xenograft mouse model, inhibited angiogenesis, and overcame taxane resistance. Our findings demonstrate the preclinical therapeutic efficacy and safety of SP-1-39, and provide support for further exploration of novel tubulin inhibitors as anti-cancer agent for cancer therapy.
Citation Format: Rui Wang, Kelli L. Hartman, Satyanarayana Pochampally, Duane D. Miller, Wei Li. SP-1-39 as a novel tubulin inhibitor overcomes taxane resistance in castration-resistant prostate cancer model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4943.
Abstract 497: HX301, a first-in-class ARK5i, demonstrates antitumor activity in preclinical HCC models with high ARK5/Myc expression
Authors: Jiao Zhihua , Wang Jingjing , Ke Hang , Zhang Faming , Li Henry 
Published: April 2023

Abstract
Introduction: Hepatocellular carcinoma (HCC) is an aggressive malignance of high mortality (6th most common worldwide) with few treatment options. Current drug treatments, including chemo-/target therapies (e.g., sorafenib), are usually ineffective among advanced HCC and with high toxicity. ARK5, or NUAK1, a novel AMP-activated protein kinase (AMPK) family member 5, is found overexpressed in many malignancies including HCC and usually associated with poor prognosis, as well as drug resistance. For example, doxorubicin, first-line chemotherapy for TACE, and transarterial chemoembolization for advanced HCC. In addition, ARK5 is found to be vitally involved in oncoprotein Myc-driven oncogenesis (metabolic homeostasis/cell survival), particularly in tumors under nutrition/oxygen-deprivations, including HCC. HX301 is a clinical stage first-in-class (FIC) ARK5 inhibitor (ARK5i) and other kinase activities (e.g., CDK4/6, CSF1R, etc.). In this study we evaluate HX301 antitumor activity in HCC over-expressing both ARK5 and c-Myc.
Methods: A panel of subcutaneous HCC patient-derived xenografts (PDXs) were genomically profiled by whole transcriptome sequencing by RNAseq, and several selected models with different expression of ARK5 and c-myc expression were assessed pharmacologically using daily dosing of 100mg/kg HX301. Subcutaneous tumor responses to HX301 were calculated by tumor growth inhibition (TGI).
Results: HCC PDX models LI1035, LI6610 both had high expression of ARK5 and Myc genes, whereas LI6650 had lower expression level of Myc than LI1035 and LI6610. LI6652 had lower expression level of ARK5 than LI1035 and LI6610. The log2 FPKM values of ARK5 and Myc in model of LI1035 was 3.9284 and 4.8177, 3.6629 and 5.3658 for LI6610, 3.1228 and -0.0556 for LI6650, -0.3538 and 6.5785 for LI6652. The TGI for LI1035 and LI6610 was 64% (P = 0.0293) and 62% (P = 0.0257) respectively whereas in comparison a smaller TGI of 44% (P = 0.034) was observed in LI6650. In the model of LI6652, TGI for HX301 was 58%, but a statistically significant difference was not observed when comparing the treatment group with the vehicle group (P = 0.138).
Conclusions: Our preliminary results demonstrate that HX301 had strong antitumor activity in HCC PDX models expressing both ARK5 and c-Myc. HX301 has the potential to be a first-in-class ARK5i candidate for the treatment of advanced HCC with high expression of c-Myc, warranting further clinical investigation.
Citation Format: Zhihua Jiao, Jingjing Wang, Hang Ke, Faming Zhang, Henry Li. HX301, a first-in-class ARK5i, demonstrates antitumor activity in preclinical HCC models with high ARK5/Myc expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 497.
Abstract 4971: Identification of statins as a potential treatment for ovarian cancer
Authors: Reilly Brendan M. , Miseirvitch Sarah J. , Walker Sarah R. 
Published: April 2023

Abstract
Late-stage diagnoses make ovarian cancer extremely hard to treat. This leads to ovarian cancer accounting for 5% of female cancer deaths and 2.5% of female cancer incidence. Since there are few options for early detection of ovarian cancer, targeted therapies could lead to better outcomes. One target that has been implicated in ovarian cancer, is the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 function is associated with tumor growth, metastasis, drug resistance, angiogenesis, and resistance to apoptosis. These many STAT3 controlled, cancer-associated cellular functions, make it an ideal and versatile target for cancer therapy. Using the Broad institute’s online C.L.U.E. tool and a STAT3 gene signature, we identified statin drugs as potential inhibitors of STAT3 activity. To assess the ability of statins to inhibit STAT3, we treated ovarian cancer spheroids with statins and analyzed STAT3 activity. We have found that statins do not induce a change in the phosphorylation of STAT3 on either tyrosine 705 or serine 727 residues, the two major sites of phosphorylation on STAT3. However, there are other poorly understood post-translational modifications of STAT3, that have previously shown effects on STAT3 function, that may be involved. Importantly, we have observed that statin treatment reduces the viability of Ovcar8 and Heya8 ovarian cancer cell spheroids. We also found that statin treatment induced apoptosis of ovarian spheroids by measuring Annexin V staining. A major problem for ovarian cancer patients is metastasis. Our preliminary evidence suggests that statins reduce the ability of ovarian cancer spheroids to clear a mesothelial monolayer of cells, an early step in ovarian cancer metastasis. There are several membrane-associated signaling proteins, including RAF and RAS, that affect STAT3 activity. Both Ovcar8 and Heya8 spheroids showed a decrease in cell viability with statin treatment, which is partially rescued by geranylgeranyl pyrophosphate (GGPP), a downstream metabolite in the mevalonate pathway. The partial recovery by GGPP indicates a mechanism involving the prenylation of membrane associated proteins. This data shows statins may provide effective treatments for ovarian cancer and defining the mechanisms behind the effects of statins may lead to better therapies and outcomes for ovarian cancer patients
Citation Format: Brendan M. Reilly, Sarah J. Miseirvitch, Sarah R. Walker. Identification of statins as a potential treatment for ovarian cancer . [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4971.
Abstract 4988: A tailored platform enables BRAF-targeted drug discovery and precision medicine
Authors: Qi Hui , Wang Fuyang , Han Bingrui , Wang Xiaomin , Qiang Xiangnan , Zhang Zhixiang , Gu Qingyang 
Published: April 2023

Abstract
Mutant BRAF, one of the most frequently mutated serine/threonine kinase, drives tumorigenesis via activating MAPK signaling across various tumor types. Expanded genomic and mechanistic studies over the past two decades have revealed the heterogeneity regarding BRAF mutation status and characterized a classification system for BRAF mutations based on their mode of action. Class I (V600 mutants) and class II (K601 mutants, G469A/V/R, etc) BRAF mutants function as RAS-independent active monomers or dimers to amplify MAPK signaling, whereas class III (G466 mutants, D594 mutants, G469E, etc) mutants, which are kinase impaired or dead, promote MAPK signaling via enhanced RAS binding and subsequent CRAF activation. To date, combination therapies of BRAF and MEK inhibitors have been approved for treatment of patients harboring class I BRAF mutations, while viable therapeutic options for those with class II and III BRAF mutations are still ambiguous. Therefore, developing new drugs and personalized therapeutic strategies directing different classes of BRAF mutations, especially class II and III subtypes, have become vital in the war against BRAF-mutant tumors. To enable BRAF-targeted drug discovery and precision medicine, we developed a tailored platform based on the classification of BRAF mutations, which integrates whole exome sequencing (WES) for identification of mutant BRAF subtypes with in vivo efficacy evaluation in patient-derived tumor xenograft (PDX) models. Our platform covers all three classes of BRAF mutants, such as V600E/G469A/D594N/G469E. Moreover, this platform faithfully recapitulate the responses of multiple targeted therapies, such as BRAF, MEK and EGFR inhibitors, reported for treating BRAF-mutant tumors in preclinical and clinical studies, highlighting the potential translation values. Taken together, the platform reported in this study empowers the discovery of novel BRAF inhibitors that can be translated into clinical trials and provides personalized therapeutic options for patients who have poorly responded to standard clinical therapies.
Citation Format: Hui Qi, Fuyang Wang, Bingrui Han, Xiaomin Wang, Xiangnan Qiang, Zhixiang Zhang, Qingyang Gu. A tailored platform enables BRAF-targeted drug discovery and precision medicine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4988.
Abstract 5010: Inhibition of discoidin domain receptor 1 (DDR1) as a new therapeutic strategy for osteosarcoma
Authors: Wang Jinglu , Walker Robert , Hornicek Francis , Duan Zhenfeng 
Published: April 2023

Abstract
Osteosarcoma is the most common type of bone cancer. Current management for osteosarcoma includes neoadjuvant chemotherapy and surgery. Unfortunately, some patients eventually develop recurrent or metastatic diseases and treatment options are extremely limited. Discoidin domain receptor 1 (DDR1) is a unique collagen-activated tyrosine kinase that participates in various human diseases, including cancer. DDR1 promotes the adhesion, proliferation, differentiation, migration, and metastasis of cancer cells. However, the expression and function of DDR1 remain unknown in osteosarcoma. The purpose of this study is to assess the expression, clinical prognostic relationship, and functional roles of DDR1 in osteosarcoma. The correlation between DDR1 expression in tumor tissues and clinicopathological features and prognosis was assessed via immunohistochemical staining of a unique tissue microarray (TMA) constructed from osteosarcoma specimens. Furthermore, DDR1 expression in osteosarcoma cell lines was determined by Western blot. DDR1-specific siRNA and a highly selective DDR1 inhibitor, 7rh, were applied to determine the impact of DDR1 expression on osteosarcoma cell growth and proliferation. In addition, the effect of DDR1 inhibition on clonogenicity was evaluated using a clonogenic assay, and a 3D cell culture model was used to mimic DDR1 effects in an in vivo environment. The results demonstrate that higher DDR1 expression significantly correlates with recurrence, metastasis, and shorter overall survival in osteosarcoma patients. The expression of DDR1 is also inversely correlated to the response to neoadjuvant chemotherapy. Therapeutically, DDR1 knockdown with siRNA or selective inhibition with 7rh decreases the proliferation and growth of osteosarcoma cells. In conclusion, our study supports DDR1 expression as an independent predictor of poor prognosis and a promising therapeutic target for osteosarcoma.
Citation Format: Jinglu Wang, Robert Walker, Francis Hornicek, Zhenfeng Duan. Inhibition of discoidin domain receptor 1 (DDR1) as a new therapeutic strategy for osteosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5010.
Abstract 5016: IL-6 influences PIM1 expression in renal cell carcinoma
Authors: Meza Kimberly S. , Holder Sheldon L. 
Published: April 2023

Abstract
Renal cell carcinoma (RCC) is the most common kidney neoplasm, accounting for over 430,000 new cases worldwide and 179,000 deaths annually. The overexpression of the proviral integration site for moloney murine leukemia virus 1 (PIM1) kinase is associated with poor clinical outcomes in patients with RCC. PIM1 is a constitutively active effector serine/threonine kinase with roles in tumor progression including cell proliferation, apoptosis, invasion, and migration. Yet, the mechanisms underlying PIM1 expression and its function in RCC are not fully delineated. IL-6 is a pleiotropic cytokine involved in the activation of the JAK/STAT signaling cascade. High serum IL-6 levels are implicated in the poor prognosis of RCC patients and are hypothesized to contribute to RCC invasion and metastasis. PIM1 is shown to be transcriptionally regulated downstream of JAK/STAT signaling and an IL-6/STAT3/PIM1 axis exists in pancreatic cancer. We thus hypothesize that this pathway also regulates expression of PIM1 in RCC. Here, we explore the levels of PIM1 in RCC and identify potential signaling pathways influencing PIM1 expression. Our results show five RCC cell lines, 769-P, 786-O, ACHN, CAKI-1, and RCC-4 cells overexpress PIM1 relative to normal renal proximal tubule epithelial cells. In RCC cell lines, IL-6 secretion correlates with PIM1 protein levels. Treatment with ruxolitinib, a JAK1/2 inhibitor, leads to a dose and concentration dependent decrease in PIM1 levels. We then tested whether incubation with an IL-6 neutralizing antibody is sufficient to regulate PIM1 protein levels. Indeed, use of an IL-6 antibody resulted in decreased pJAK2 protein and PIM1 protein. Our initial studies suggest that differential expression of PIM1 among RCC cell lines may be linked to autocrine IL-6 signaling. Interestingly, 769-P cells demonstrate increased PIM1 levels but do not secrete IL-6 and neither ruxolitinib treatment nor incubation with an IL-6 neutralizing antibody appear to affect PIM1 levels. Therefore, an IL-6/JAK-independent pathway resulting in increased PIM1 protein levels likely exists in 769-P cells. Further investigation is required to elucidate the contexts of PIM1 regulatory pathways in order to develop novel targeted anti-cancer strategies in RCC.
Citation Format: Kimberly S. Meza, Sheldon L. Holder. IL-6 influences PIM1 expression in renal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5016.
Abstract 5024: Role of protein kinase C ζ and ι inhibitors on ovarian cancer cell lines in combination with cisplatin
Authors: Marzan Mahfuza , Oishee Nuzhat Nowshin , Khalid Khandker Mohammad , Acevedo-Duncan Mildred 
Published: April 2023

Abstract
Ovarian cancer causes more death than any other cancers of the female reproductive system. Current treatment strategies are surgical removal of cancerous parts and chemotherapy with platinum drugs (e.g. cisplatin, carboplatin) or taxols. However, recurrence of cancer with drug resistance is frequent. Previously two inhibitors; ICA-1S (5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide and ζ-stat (8-hydroxy-1,3,6- naphthalenetrisulfonic acid) specific for two atypical protein kinases, PKC-ι and PKC-ζ respectively have been reported. These inhibitors have an anticancer effect in different cancers, including clear-cell ovarian cancer. Our aim was to find if cisplatin has any synergistic effect with ICA-1S and ζ-stat on ovarian cancer cell proliferation, migration, and apoptosis. Ovarian cancer cell line ES-2, which has mutation in p53 gene was used in this study. After 72 hours of treatment with ICA-1S (10 µM) and ζ-stat (10 µM), proliferation of ES-2 cell line was inhibited by 42.5% and 23.5% respectively compared to control. When combined with cisplatin (0.5 µM), the inhibition of cell proliferation increased to 67% for ζ-stat and 65.8% for ICA-1S (N=3 trials) which is synergistic. Wound healing assay with ES-2 cells showed that ICA-1S and cisplatin inhibited the migration of ES-2 cells separately as well as in combination. SDS-PAGE and subsequent western blotting showed that ICA-1S monotherapy and combination with cisplatin reduced the expression mutant p53, PI3K, AKT, Bcl2, and phopho-BAD. IP with PKC ζ beads showed the association of PKC ζ with PKC-ι and p53 in ES-2 cell line. As mutation in p53 is quite frequent in ovarian cancer with gain of function, ICA-1S may have an advantageous role in inhibiting mutated p53 regulated pathway. Inhibition of ES-2 cell line with ICA-1S and ζ-stat also suggested that PKC-ι and PKC ζ play important roles in ovarian cancer and may augment traditional chemotherapy. Further study on the pathway affected by aPKC inhibitors combined with cisplatin would be investigated through WST, western blotting and immunoprecipitation assay.
Citation Format: Mahfuza Marzan, Nuzhat Nowshin Oishee, Khandker Mohammad Khalid, Mildred Acevedo-Duncan. Role of protein kinase C ζ and ι inhibitors on ovarian cancer cell lines in combination with cisplatin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5024.