Correction: Mandal et al. Modified Linear Peptides Effectively Silence STAT-3 in Breast Cancer and Ovarian Cancer Cell Lines. Pharmaceutics 2023, 15, 666

Adenoviral vectors with E1A regulated by tumor-specific promoters are selectively cytolytic for breast cancer and melanoma.

Four breast cancer cell lines (MCF-7, BT-549, MDA-MB-231 and T-47D) and four ovarian cancer cell lines (1A9/A2780, ES-2, MES-OV and OVCAR-3) were selected for taxane resistance by exposing cells to either docetaxel or paclitaxel in the presence of the P-glycoprotein inhibitor, PSC-833 (valspodar, 2 μM). All of these co-selected variants are MDR1/ABCB1(-), and the resistance to taxanes is not transporter-mediated. We have previously reported elevated class III β-tubulin (TUBB3), reduced BRCA1, elevated CDKN1A (p21), and altered epithelial-mesenchymal transition (EMT) genes in the majority of the non-MDR1 taxane variants. Inhibitors of apoptosis (IAP) proteins directly bind and inhibit several caspases, and may play a critical role in determining cell fate after exposure to chemotherapeutic agents. In this study, we profiled the expression of IAP proteins and found elevated content in this panel of taxane-resistant human breast and ovarian cancer cell lines. In both the paclitaxel- (TP) and docetaxel-selected (TxTP) ovarian cancer cell lines we observed significantly overexpressed cIAP1 (BIRC2), cIAP2 (BIRC3), XIAP (BIRC4), and Livin (BIRC7) relative to parental cell lines. Expression of cIAP2 was undetectable in OVCAR-3 and its taxane resistant cell lines, OVCAR-3/TP20 and OVCAR-3/TxTP5. Elevated cIAP1 and XIAP levels were detected in the human breast cancer variant BT-549/TxTP50, and Livin was overexpressed in all taxane-resistant breast cancer cell models. Survivin (BIRC5) is highly expressed in cancers and has been associated with taxane resistance via its effects on apoptosis and the cell cycle. We observed reduced Survivin content in the majority of the variants established in our laboratory except for the ovarian ES-2/TP80 cell line where we found slightly elevated expression resulting from paclitaxel selection relative to its parental control. In addition to these alterations in IAP content, we observed elevated Bcl-2 in ovarian (MES-OV/TP40 and MES-OV/TxTP50) and breast (MCF-7/TxTP50, BT-549/TxTP50, and MDA231/TxTP50) cancer cell lines at the transcript level by rt-PCR and confirmed by immunoblotting. Specific gene silencing by RNAi and treatment with small molecule inhibitors will test the functional significance of IAP alterations in these models of taxane resistance. Citation Format: George E. Duran, Anamaria Brozovic, Francisco J. Martinez, E Brian Francisco, Yan C. Wang, Branimir I. Sikic. Overexpression of inhibitors of apoptosis (IAP) family members in human breast and ovarian cancer models of non-MDR1 taxane resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 901. doi:10.1158/1538-7445.AM2013-901

Introduction: In women, breast cancer is the most prevalent cancer diagnosis while ovarian cancer represents the most lethal gynecological neoplasm. Together, these cancer types place a huge burden on society, comprising 20% of all estimated cancer deaths in the USA for 2012. The high incidence and mortality rates of these cancer types, in addition to the emergence of multi-drug resistant variants, highlights the need to develop novel therapeutic agents with greater efficacy. Artesunate (ART) is a semi-synthetic derivative of artemisinin, a natural compound derived from the Chinese herb Artemisia annua L. ART is an antimalarial agent that also possesses potent anticancer activity. Since the use of ART as an antimalarial agent is associated with few adverse effects, ART may represent a less toxic alternative to conventional chemotherapy. This study investigates the cytotoxic effects of ART on breast and ovarian cancer cell lines and the mechanisms underlying its activity. Methods & Results: ART exhibited a dose- and time-dependent effect on a panel of breast and ovarian cancer cell lines. Anticancer activity was also observed in 3-D cultures of both cancer cell types. Oregon Green 488 and propidium iodide (PI) staining of cancer cells revealed that ART strongly inhibited cancer cell proliferation, arresting cells in the G1 or G2 phases of the cell cycle. ART-mediated G2 arrest was dependent on reactive oxygen species (ROS), as in the presence of an antioxidant all cell lines arrested in G1. ART's antiproliferative effect was due in part to its ability to modulate the expression of cell cycle regulatory proteins including cyclin D3, p21, CDK4 and CDC25C. Annexin V/PI staining of ART-treated cancer cells revealed that ART induced ROS-dependent apoptosis in both breast and ovarian cancer cell lines. Pretreatment of cancer cells with a pan-caspase inhibitor decreased but did not eliminate ART-induced cytotoxicity, suggesting that caspase-dependent apoptosis is one of several pathways involved in ART-mediated killing of cancer cells. ART caused ROS-dependent DNA damage indicated by the presence of γH2AX, which implicates the DNA damage pathway in ART-induced cancer cell death. Annexin V/PI staining of ART-treated normal dermal fibroblasts and human mammary epithelial cells demonstrated that ART had limited cytotoxicity for normal cells at doses that were toxic to cancer cells, highlighting an increased sensitivity of cancer cells to ART treatment. Conclusions: These data show that ART has a potent antiproliferative and cytotoxic effect on both breast and ovarian cancer cells with limited cytotoxicity for normal cells. ART's specific cytotoxic activity and excellent safety record in malaria patients make it a worthy candidate for further investigation as a possible treatment for breast and ovarian cancer. Supported by NSERC and the CBCF-Atlantic Region Citation Format: Anna L. Greenshields, David Hoskin. Anti-proliferative and cytotoxic activities of the anti-malarial compound artesunate for breast and ovarian cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2262. doi:10.1158/1538-7445.AM2013-2262

Breast cancer is the most common cause and epithelial ovarian cancer the fourth most common cause of cancer death among women in the developed world. While breast cancer can be cured in 70% of cases, only 30% of ovarian cancer patients remain free from disease long term. Paclitaxel is an integral component of primary therapy for both forms of cancer, but less than half of breast and ovarian cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. In recent years several kinases have been identified that regulate the sensitivity of cancer cells to paclitaxel by inhibiting centrosome splitting or enhancing microtubule stability. Much less attention has been given to kinases that affect paclitaxel sensitivity by modulating cancer cell metabolism. We previously performed siRNA kinome-screens to identify molecular targets whose decreased expression overcomes paclitaxel resistance and increases paclitaxel sensitivity in ovarian cancer cells. We showed that 20% of the potential kinase targets whose knockdown modulates paclitaxel sensitivity participate in glucose and energy metabolism. Among these, a leading candidate was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), an isoform of the glycolytic enzyme phosphofructokinase (PFK2). PFKFB2 is overexpressed in a fraction of ovarian and breast cancers. Knockdown of PFKFB2 inhibited clonogenic growth of ovarian and breast cancer cell lines and enhanced paclitaxel sensitivity in the cell lines with wt TP53. Liposome encapsulated PFKFB2 siRNA significantly inhibited tumor growth and enhanced sensitivity to paclitaxel in xenografts derived from ovarian cancer cell lines. Knockdown of PFKFB2 increased glycolysis, decreasing the flow of glycolytic intermediates to the pentose-phosphate pathway with reduced G6PD activity in wt TP53 cancer cell lines. With decreased NADPH, ROS accumulated after PFKFB2 knockdown, stimulating phosphorylation of JNK, inducing G1 cell cycle arrest, and initiating apoptosis dependent upon upregulation of p21Cip1 and Puma which are downstream targets of TP53. Our studies have shown for the first time that PFKFB2, a glycolytic enzyme, drives tumor cell growth and regulates paclitaxel sensitivity by inducing apoptosis and G1 cell cycle arrest. These findings highlight a remarkable degree of coordination between cancer metabolism with cell proliferation and chemo-sensitivity, which may provide a novel target in patients with ovarian cancers and breast cancers where TP53 function remains intact. Citation Format: Hailing Yang, Shu Zhang, Weiqun Mao, Ahmed A. Ahmed, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Anil K. Sood, Xiao-Feng Le, Zhen Lu, Robert C. Bast. Silencing pfkfb2 enhances paclitaxel sensitivity by modulating metabolism of p53 wt ovarian and breast cancer cells and xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3564. doi:10.1158/1538-7445.AM2017-3564

Breast cancer is the most commonly diagnosed cancer among women and holds a significant place among cancer-related mortalities worldwide. Ovarian cancer, on the other hand, is often diagnosed at an advanced stage and is known to have the highest mortality rate among gynecological malignancies. Traditional cancer treatment methods, including surgery, chemotherapy, and radiotherapy, are widely used; however, these approaches are associated with high costs and can also cause severe side effects by damaging healthy cells. This has increased the need for more targeted therapeutic strategies with reduced side effects. In recent years, plant- derived radiolabeled compounds have emerged as an innovative approach, offering a more effective treatment by selectively targeting cancer cells while minimizing adverse effects on healthy tissues. This study aims to evaluate the anticancer potential of Pinus pinea (Stone Pine) needle extract by radiolabeling it with Iodine-131 (¹³¹I), a commonly used radioisotope in nuclear medicine. Pinus pinea contains bioactive compounds such as flavonoids, phenolic compounds, and terpenoids, which exhibit antioxidant, anti-inflammatory, and anticancer properties. However, scientific data on the anticancer potential of Pinus pinea needles remain limited. Within the scope of this study, Pinus pinea needle extract was obtained, and its quality control was performed using High-Performance Liquid Chromatography (HPLC) and Liquid Chromatography–Mass Spectrometry (LC/MS-QTOF) techniques. The obtained Pinus pinea needle extract was evaluated using a nuclear method, radiolabeling with Iodine-131 (¹³¹I) (t₁/₂: 8.02 days), which is widely utilized in nuclear medicine for diagnostic and therapeutic purposes. The radiolabeling efficiency of the compound was assessed using Thin Layer Radiochromatography (TLRC), and the chromatograms indicated a radiolabeling yield exceeding 95% (n=3). Future studies will involve in vitro cytotoxicity and apoptosis analyses in breast cancer (MCF-7) and ovarian cancer (SKOV-3 and MDAH-2774) cell lines. Additionally, the in vitro bioactivities of the Pinus pinea needle extract will be further evaluated using the radioiodination method. Moreover, the design of advanced studies involving in vivo animal models is planned, allowing comparisons between in vivo and in vitro results. This study highlights the anticancer potential of Pinus pinea needle extract and demonstrates the potential application of plant-derived radiolabeled compounds in nuclear medicine. The findings provide a foundation for further research on the effects of Pinus pinea extract on breast and ovarian cancer cell lines, suggesting that such bioactive compounds may offer a novel alternative in cancer treatment.

The effect of antibodies and immunotoxins reactive with HER-2/ neu on growth of ovarian and breast cancer cell lines

One important and high-yielding paradigm in the development of novel, targeted anticancer therapies is to identify genes that are not essential to normal cells but that have become critically important to particular cancer cells as they rely on these genes for survival. This concept, sometimes called addiction of cancer cells to specific genes or pathways can be exploited in the clinic because the function of the genes that cancer cells are addicted to can be disrupted using genetic or chemical manipulation, leading to selective killing of cancer cells while normal cells are minimally affected. For example, it was shown that homologous recombination-defective BRCA1-deficient cancer cells rely heavily on other repair pathways such as NHEJ, one of the pathways facilitated by PARP1. This finding has led to clinical trials designed to determine if PARP inhibitor drugs are an effective treatment for patients with BRCA1-deficient breast and ovarian cancer. We have previously discovered, via a high throughput screen, that simultaneous deficiency in BRCA1 and the WRN RECQ helicase resulted in additive growth-suppressive phenotype in human fibroblasts. WRN is a gene mutated in the Werner syndrome of premature aging, and it is a multifunctional exonuclease/helicase involved in maintenance of genomic stability. Congenital loss of WRN also predisposes to sarcomas and melanomas, though interestingly, not to the most common type of age-related cancer – carcinoma. Near-complete inactivation of WRN in human fibroblasts and common cell lines such as sarcoma-derived U2OS and HT1080, is typically non-lethal, though somewhat reduces cellular growth rate and fitness. Following our original observation, we were interested to determine whether loss of WRN is synthetically lethal with loss of BRCA1 in breast and ovarian cancer cell lines, and if loss of WRN restores sensitivity to platinum or impairs growth in platinum resistant clones derived from breast and ovarian cancer cell lines. Our results show that depletion of WRN in BRCA1-negative or positive breast or ovarian cancer cell lines dramatically suppresses their growth. Both in breast and ovarian cancer cells, at least some of this growth suppression could be attributed to the induction of RNAi-triggered cytotoxicity by WRN downregulation. In addition, WRN depletion also hypersensitized the HCC1937 breast cancer cell line to platinum, however this effect of WRN was attenuated in platinum-resistant clones derived in vitro from this line. Strikingly, non-cancerous mammary epithelial line MCF10a showed virtually no growth suppression by WRN depletion, suggesting that breast and ovarian cancer cells may be more reliant on WRN than normal cells of at least some of the relevant epithelial lineages — which is a therapeutically exploitable trait. We are currently following up on this observation using other non-cancerous epithelial cells, such as primary mammary and fallopian tube epithelial cells, as well as primary human keratinocytes. We will present these data as well as the update on reproducing WRN growth-suppressive phenotype using small molecule inhibitors of WRN. Significance: Our results highlight WRN as a potential novel target for development of breast and ovarian cancer therapies. Citation Format: Piri Welcsh, Keffy Kehrli, Paul Lazarchuk, Julia Sidorova. Growth-suppressive effect of WRN RECQ helicase inactivation in breast and ovarian cancer cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1346.

Bipterostilbene, a Novel Compound From Rhubarb, Specifically Inhibits the Proliferation of Malignant B Cells Via Inactivation of AKT/mTOR Signaling Pathway

RNA interference (RNAi) has drawn enormous attention as a powerful tool because of its capability to interfere with mRNA and protein production. However, designing a safe and efficient delivery system in RNAi therapeutics remains challenging. Herein, we have designed and synthesized several linear peptides containing tryptophan (W) and arginine (R) residues separated by the β-alanine (βA) spacer and attached to a lipophilic fatty acyl chain, cholesterol, or PEG. The peptide backbone sequences were: Ac-C-βA-βA-W4-βA-βA-R4-CO-NH2 and Ac-K-βA-βA-W4-βA-βA-R4-CO-NH2, with only a difference in N-terminal amino acid. The cysteine side chain in the first sequence was used for the conjugation with PEG2000 and PEG550. Alternatively, the side chain of lysine in the second sequence was used for conjugation with cholesterol or oleic acid. We hypothesized that amphiphilic peptides and optimum fatty acyl chain or PEG could function as an effective siRNA carrier by complementing each structural component’s self-assembly and membrane internalization properties. None of the designed peptides showed cytotoxicity up to 10 µM. Serum stability studies suggested that the newly designed peptides efficiently protected siRNA against early degradation by nucleases. Flow cytometry analysis indicated 50–90% cellular uptake of siRNA using the newly developed modified linear peptides (MLPs). Western blot results revealed more than 90% protein downregulation after targeting STAT3 in MDA-MB-231 and SKOV-3 cell lines. In summary, a new peptide class was developed to safely and efficiently deliver siRNA.

The objective of this study was to develop an adenoviral vector system that would generate a pattern of expression of exogenous therapeutic genes appropriate for the treatment of ovarian cancer. For this purpose, we have generated a replication-deficient recombinant adenoviral vector, AdLPLacZ, which contains the human L-plastin (LP) promoter (LP-P) driving the Escherichia coli LacZ gene. LP is constitutively expressed at high levels in malignant epithelial cells but is not expressed in normal tissues, except at low levels in mature hematopoietic cells. Because adenoviral vectors infect early hematopoietic multilineage precursor cells only poorly or not at all, this vector would be of use in the peritoneal cavity and in vitro for marrow purging. We first analyzed the expression of the LacZ reporter gene in ovarian and breast cancer cell lines, normal fibroblasts, and leukemia cell lines using the adenoviral vector in which the LacZ gene is governed by the LP-P promoter (AdLPLacZ) or in which the LacZ gene is governed by the cytomegalovirus (CMV) promoter (AdCMVLacZ). We found equivalent and high levels of expression of beta-galactosidase (beta-gal) by AdLPLacZ and AdCMVLacZ vectors in the breast or ovarian cancer cell lines as well as in a fibrosarcoma cell line, indicating that the adenoviral vectors infected these cells and expressed their transgenes equally with the LP and CMV promoters. Expression of the LacZ gene with the CMV vector but not with the LP-P vector was observed in experiments with normal fibroblasts, indicating that the vectors infected the cells, but that the LP-P was not active within them. In hematopoietic cells such as U937 cells, no measurable beta-gal activity was detected in cells infected either by AdLPLacZ or by AdCMVLacZ, indicating that the adenoviral vectors were not infecting the cells. Although beta-gal activity was observed in fresh ascitic ovarian cancer cells after infection with adenoviral vectors containing CMV or the LP promoters, beta-gal activity was detected in a portion of a biopsy of normal peritoneum when the tissues were exposed to the AdCMVLacZ vector, but not when tissues were exposed to the AdLPLacZ vector. These results suggest that the transcription of therapeutic genes in cells infected by the AdLP vectors would be restricted to LP expression-positive ovarian carcinoma cells but would not be seen in the normal mesothelial cells of the peritoneal cavity. This possibility implies that adenoviral vectors carrying therapeutic genes driven by the LP-P would be of use for the intracavitary treatment ovarian cancer.

1944P - Pharmacological screening with Chk1 inhibitors identifies synergistic agents to overcome resistance to platinums in basal breast and ovarian cancer

To compare biological properties of primary tumor cells isolated from malignant effusion of cancer patients with the same cells of permanent lines established during their long-term cultivation in vitro and to assess the impact of phenotypic conversion that was caused by changes in their microenvironment on their behavioral characteristics. The study was performed on primary cell cultures from pleural effusion or ascites of breast and ovarian cancer and permanent cell lines derived from them, namely permanent ovarian cancer cell line I, permanent ovarian cancer cell line II and permanent breast cancer cell line I. Biological characteristics were studied using standard cell culture methods and immunocytochemical assays. Three new cell lines were established from breast and ovarian cancer and cell morphology, migration activity, the kinetics of growth, colony forming activity in semisolid agar and sensitivity to anticancer drug were examined. These characteristics were compared with those of the primary tumor cells. It has been shown that among the primary tumor cells from malignant effusion, cells with mese-nchymal characteristics were the most prevalent. Cultivation of primary cancer cells in vitro leads to a phenotypic change of their population: it becomes more homogeneous in morphology with predominantly epithelial-like cells. Also, later after a number of cell doublings in vitro, the cell population changes to include cells primarily with immunophenotypic properties characteristic of epithelial cells. These changes include increase in number of E-cadherin-positive cells and a decrease in number of vimentin and α- smooth muscle actin-positive cells. It was found that significant changes in expression of epithelial-mesenchymal transition associated proteins in cells during their cultivation in vitro in new microenvironment are accompanied by a rapid change in their sensiti-vity to anticancer drugs. The new breast and ovarian cancer cell lines were established and characterized. The induction of phenotypic transdifferentiation in malignant cells from pleural effusion and ascites can be an important approach for suppressing the progression of neoplastic process.

Expression of active plasminogen activator inhibitor-1 reduces cell migration and invasion in breast and gynecological cancer cells

Expression of icb-1 gene is interferon-gamma inducible in breast and ovarian cancer cell lines and affects the IFNγ-response of SK-OV-3 ovarian cancer cells

Epithelial ovarian cancer is the fourth most common cause of cancer death among women in the developed world. Currently only 30% of ovarian cancer patients remain free from disease long term. Paclitaxel is an integral component of primary therapy for ovarian cancer, but less than half of ovarian cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with the disease. In recent years, we have identified several kinases that regulate the sensitivity of cancer cells to paclitaxel by modulating cancer metabolism, enhancing microtubule stability, inhibiting centrosome splitting or blocking AKT/survivin signaling. We performed siRNA kinome-screens to identify molecular targets whose decreased expression overcomes paclitaxel resistance and increases paclitaxel sensitivity in ovarian cancer cells. Upon assessing cell viability, we showed that 20% of the potential kinase targets whose knockdown modulates paclitaxel sensitivity participate in glucose and energy metabolism. Among these, a leading candidate was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), an isoform of the glycolytic enzyme phosphofructokinase (PFK2). Many cancer cells depend on glucose for survival. Glycolysis involves ten metabolic reactions catalyzed by enzymes whose expression is frequently increased during malignant transformation. Many reports document the role of oncogenic signaling in regulating the activity of metabolic enzymes to support the enhanced macromolecule synthesis required for rapid proliferation of cancer cells. Cancer cells express altered levels of the different PFK-2/FBPase-2 isoenzymes and even modulate their relative kinase and bisphosphatase activities according to metabolic needs in a spatial and/or temporal manner. PFKFB2 is a bifunctional glycolytic enzyme that regulates the level of fructose-2,6-bisphosphate (Fru-2,6-BP) and is overexpressed in a fraction of ovarian and breast cancers. We found that knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP553). Additionally, PFKFB2 siRNA or PFKFB2 shRNA significantly inhibited tumor growth and enhanced sensitivity to paclitaxel in xenografts derived from two ovarian cancer cell lines. Knockdown of PFKFB2 increased the rate of glycolysis, but decreased the flow of intermediates through the pentose-phosphate pathway in cancer cell lines with wtTP53, decreasing NADPH. Reactive oxygen species (ROS) accumulated after PFKFB2 knockdown, which stimulated phosphorylation of Janus kinase (JNK), induced G1 cell cycle arrest, and initiated apoptosis that depended upon upregulation of p21Cip1 and Puma. Thus, PFKFB2 is a glycolytic enzyme that drives tumor cell growth and enhances paclitaxel resistance by inhibiting TP53-dependent G1 cell cycle arrest and apoptosis. These findings highlight the interaction of cancer-altered metabolism with cell proliferation and chemosensitivity, which may provide a novel target in patients with ovarian and breast cancers where TP53 function remains intact. We also found that knockdown of kinases that regulate microtubule stability could sensitize ovarian cancer cells to paclitaxel treatment. In previous studies, baseline microtubule stability correlated with response to paclitaxel in ovarian cancer cell lines and both parameters could be enhanced by knockdown of individual kinases. Using the initial 14 kinase targets, we performed assays of microtubule stability, apoptosis, and cell cycle arrest with all possible pairs of kinase siRNA which enhance paclitaxel sensitivity across multiple cell lines and found that dual knockdown of IKBKB/STK39 had the greatest effect on enhancing paclitaxel stability. Our study documents the impact of sequentially silencing IKBKB and STK39 on paclitaxel sensitivity, providing a rationale for siRNA-based therapy. Different siRNAs are in the developmental pipeline for a variety of diseases including cancer, and more than a dozen are in phase I or II clinical trials. One of the most promising candidates to emerge from our kinase screen was salt inducible kinase 2 (SIK2), a serine/threonine kinase that is required for bipolar mitotic spindle formation and normal mitotic progression. With Dr. Ahmed Ahmed, we previously found knockdown of SIK2 induces polyploidy by blocking centrosome splitting and inhibits PI3K, sensitizing cells to paclitaxel. We demonstrated that knockdown of SIK2 inhibits xenograft growth and potentiates paclitaxel activity in vivo. Subsequently, we have partnered with Arrien Pharmaceuticals to test a small-molecule inhibitor of SIK2. We have found that novel SIK2 inhibitors, ARN-3236 and ARN3261, block the activity of SIK2 kinase and inhibit ovarian cancer cell growth, enhancing paclitaxel sensitivity in cultured cells and in xenografts. ARN-3261 will enter first-in-human trials at MD Anderson early next year. Taken together, our results support the development of small-molecule kinase inhibitors that modulate glycolysis, enhance microtubule stability, induce polyploidy, and inhibit AKT/survivin signaling, providing novel routes to enhance primary paclitaxel-based therapy for ovarian cancer and to improve patient outcomes. Citation Format: Zhen Lu. Kinase-mediated modulation of paclitaxel sensitivity in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA08.