In vivo activity of R1530 (R) alone and in combination with docetaxel (D) and bevacizumab (B) in a prostate carcinoma (PCa) xenograft model

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16124-e16124
Author(s):  
K. D. Kolinsky ◽  
Y. Zhang ◽  
K. Packman ◽  
B. Higgins
Keyword(s):  
Xenograft Model ◽  
Optimal Dose ◽  
P Value ◽  
Clinical Testing ◽  
Cancer Cell Growth ◽  
Multikinase Inhibitor ◽  
R And D ◽  
Final Study ◽  
M Phase

e16124 Background: R is a multikinase inhibitor currently in phase I clinical testing. Its inhibitory profile includes several kinases that play critical roles in cancer cell growth and division leading to disruption at M-phase and antiangiogenic effects. Studies were conducted to evaluate the efficacy and tolerability of R alone and in combination with D and B in the 22rv1 androgen independent PCa model. Methods: Initially TGI of optimal dose (OD) R, D and B were evaluated. Then the TGI and increased life span (ILS) of the minimum efficacious dose (MED) and 2/3 OD R ± 2/3 OD D was tested. A final study compared doublets of 2/3 OD R + 2/3 OD D, 2/3 OD D + OD B, 2/3 OD R + OD B, and triplet of 2/3 OD D + 2/3 OD R+ 2/3 OD B. Results: All treatment groups were tolerated and there was no antagonism. TGI and ILS results are listed below ( Table ). Conclusions: The OD of R B and D showed monotherapy TGI in this model. MED R + 2/3 OD D gave ILS statistically better (sb) than singlets but TGI was sb than MED R but not the D singlet. 2/3 OD R + 2/3 OD D produced sb TGI and ILS than each singlet. TGI and ILS with 2/3 OD R is sb than 2/3 OD D. TGI and ILS of 2/3 OD R + 2/3 OD D was sb than the 2/3 OD D + OD B but not the 2/3 OD R + B doublet. TGI and ILS was sb for 2/3 OD R + OD B versus 2/3 OD D + OD B. The TGI of the triplet was equivalent to the 2/3 OD R + 2/3 OD D doublet, but ILS was sb in the triplet. Also, the TGI and ILS was sb for triplet versus 2/3 OD D + OD B. TGI and ILS of the triplet was equal to 2/3 OD R + OD B. In general, the results demonstrate that the shared mechanism of mitotic disruption by R and D do not render antagonism, but in fact, allow for potentiated TGI and ILS. Also of note is the equally superior TGI and ILS provided by R + B and R + B + D. In general, the preclinical results generated support clinical testing of these agents in PCa. * p value for all. [Table: see text] [Table: see text]

scholarly journals Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 672 ◽  
Author(s):  
Roberta Affatato ◽  
Laura Carrassa ◽  
Rosaria Chilà ◽  
Monica Lupi ◽  
Valentina Restelli ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
High Throughput Screening ◽  
Therapeutic Option ◽  
Xenograft Model ◽  
Antimitotic Drugs ◽  
M Phase ◽  
Sirna Library

Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.

Polo-Like Kinase-1 (Plk-1) Inhibitor BI 2536 Induces Mitotic Arrest and Apoptosis in Vivo: First Demonstration of Target Inhibition in the Bone Marrow of AML Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2641-2641
Author(s):  
Kang-Hun Lee ◽  
Richard F. Schlenk ◽  
Gesine Bug ◽  
Carsten Müller-Tidow ◽  
Ralph M. Waesch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Response ◽  
Peripheral Blood ◽  
Histone H3 ◽  
Mitotic Arrest ◽  
Clinical Testing ◽  
Facs Analysis ◽  
M Phase ◽  
Bi 2536

Abstract Background: BI 2536 is a potent and selective inhibitor of Plk-1, which plays a crucial role in the regulation of mitosis. Inhibition of Plk-1 leads to mitotic arrest and apoptosis. Therefore, Plk-1 inhibitors are currently in clinical testing as anti-proliferative agents in cancer patients. BI 2536, the first specific Plk-1 inhibitor in clinical testing, demonstrated strong anti-proliferative effects on AML cell lines in vitro and in in vivo models. To investigate target inhibition in the malignant cell, bone marrow samples from patients who participated in a Phase I/II study of BI 2536 single-agent therapy in elderly patients with relapsed or refractory AML were analyzed. Methods: Pharmacodynamic analyses including immunocytochemistry (ICC) and flow cytometry (FACS) of bone marrow (BM) were performed to examine cell morphology, phosphorylation of histone H3 (phospho-H3), and induction of apoptosis. Samples were acquired before and 24 h after the first administration of BI 2536. FACS analysis included propidium iodide (PI)-FACS to determine the percentage of cells residing in various cell cycle stages (G0/1-, S- and G2/M-phases) and Annexin V-Cy5-staining for apoptosis. Immunocytochemistry included staining for phosphorylated histone H3 and TUNEL assay for apoptosis. Results: At the time of analysis, data from 28 patients treated at doses in the range of 50 to 400 mg BI 2536 were available. BM taken after BI 2536 administration showed an increase of phospho-H3 positive cells as compared to baseline prior to treatment. There was a trend toward a positive correlation between phospho-H3 increase and increase in dosage of BI 2536 (p=0.16) when treatment at low doses (50 to 60 mg) of BI 2536 were compared to treatment at higher doses (100 to 400 mg). Furthermore, trends were observed that an increase of phospho-H3 is positively correlated with both a higher percentage of cells in G2/M and an increase in apoptotic cells. The typical morphology of cells in mitotic arrest could be demonstrated by ICC. Interestingly, when patients with progressive disease after one cycle (PD) were compared to patients with disease stabilization or response (nonPD), a statistically significant positive correlation between PD and increase in phospho-H3 compared to baseline was found (p=0.03). Also, there was a clear trend for an increase in the percentage of cells in G2/M phase and apoptosis in patients with PD compared to patients with nonPD. Preliminary evaluation of other disease characteristics including karyotype (normal vs complex), secondary AML, complete response in previous treatments, baseline value for blasts in the bone marrow or in the peripheral blood, did not reveal any signs of correlation with the clinical response to BI 2536 treatment. Conclusion: BI 2536 treatment increases the number of cells in G2/M phase (as detected by FACS analysis and phospho-H3 staining) and the number of apoptotic cells within 24 h after administration. In line with the clinical observation of rapid blast reduction both in the BM and the peripheral blood, these findings indicate that BI 2536 induces mitotic arrest and apoptosis of the malignant target cells in AML patients. The biological meaning of the correlation between the BM findings and the clinical response to BI 2536 is unclear, but if substantiated by more data, these results may suggest a predictive value of BM examinations for the response to BI 2536.

Efficacy of vemurafenib (V), a selective V600EBRAF inhibitor, as monotherapy or in combination with erlotinib (Erl) or erbitux (Erb) and irinotecan (Iri) doublets and triplets in a colorectal cancer (CRC) xenograft model.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 494-494
Author(s):  
Brian Higgins ◽  
Kenneth Daniel Kolinsky ◽  
Kathleen Schostack ◽  
Gideon Bollag ◽  
Richard J. Lee ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mapk Pathway ◽  
Single Agent ◽  
Xenograft Model ◽  
Optimal Dose ◽  
Tumor Growth Inhibition ◽  
Egfr Inhibition ◽  
Final Study ◽  
Molecule Inhibitor ◽  
Better Than

494 Background: B-Raf mutations, particularly at V600 occur in 10% of CRCs resulting in constitutive activation of the MAPK pathway. V (RG7204, PLX4032) is a first-in-class, V600B-Raf-selective small molecule inhibitor previously shown to potentiate anti-tumor effects in the V600E CRC xenograft model HT29 in combination (combo) with capecitabine ± bevacizumab (ASCO GI, 2008). V600E CRC respond poorly to EGFR inhibition (EGFRi) both preclinically and clinically. We aimed to determine whether antitumor activity could be potentiated by combining V with EGFRi. Methods: The monotherapy (mono) activities of V, Erl, Erb and Iri were compared to combo of these agents in the HT29 model. V was tested as a mono at its optimal dose (OD), Erl was tested at its MTD or 2/3 MTD, and a combo of V OD + 2/3 MTD Erl were tested. V was subsequently tested as mono or combo at the OD and suboptimal-OD with OD Erb. A final study included Iri as mono, doublets of Iri + V or Erb, and triplet combo of Iri, V, and Erb. Results: Tumor growth inhibition (TGI) and increase in life span (ILS) for combo of OD V + 2/3 MTD Erl was superior to all mono arms. TGI in mono arms was equivalent for V, Erb and Iri. ILS was better for V vs Iri and Erb mono, while Iri vs Erb ILS were equivalent. TGI and ILS for Iri + Erb doublet was equivalent to V mono. Otherwise, TGI and ILS in all other doublets and triplets were superior to mono groups. TGI in V + Erb and V + Iri were equivalent, but ILS was better for V + Iri. TGI and ILS for V + Iri was better than Iri + Erb. TGI in V + Erb was better than Iri + Erb, but ILS was equivalent. TGI in the triplet was superior to all doublets except V + Erb, however ILS was superior to all doublets tested. Conclusions: V potentiates anti-tumor activity in a V600E CRC model when used in combo with Erl, Erb and Iri. Although a V + Erb doublet provided impressive TGI equivalent to a triplet with Iri, the triplet yielded sustained antitumor activity as demonstrated by a significant increase in survival as compared to the doublet. Combo with V may afford V600E CRC patients a differential response to what is seen traditionally with single agent EGFi and is worthy of clinical exploration.

Comparing surgical tissue versus biopsy tissue in the development of a clear cell renal cell carcinoma xenograft model.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 519-519
Author(s):  
Yiyu Dong ◽  
Brandon Manley ◽  
A. Ari Hakimi ◽  
Jonathan A. Coleman ◽  
Paul Russo ◽  
...  
Keyword(s):  
Xenograft Model ◽  
In Vivo Model ◽  
P Value ◽  
Cell Renal Cell Carcinoma ◽  
Immunodeficient Mice ◽  
Biopsy Tissue ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Selection Of

519 Background: The use of xenograft tumor models is considered the ideal platform to investigate the effects and toxicities of novel drugs in primary human tumors. The establishment of a personalized xenograft model using preoperative or pretherapy biopsy for patients with metastatic or high risk disease could improve selection of targeted therapy. We report on our xenograft model using various tissue sources including biopsies and correlation with patient’s clinical features. Methods: 56 specimens from primary and metastatic ccRCC from 48 patients were collected. After surgery (n=35) or biopsy (n=21) the specimen was transplanted either subcutaneously or after cell culture to immunodeficient mice. Tumor engraftment was followed for up to 4 months. Successfully engrafted patient-derived tumors were passaged to further mice. Conformation of xenograft tumors with formalin-fixed, paraffin-embedded and Hematoxylin and eosin stained tumor sections was done to assure morphological concordance with the patients tumor. We used a two-tailed two proportion z-test to compare the number of successful xenografts harvested from surgical tissue or biopsy tissue. Results: Overall 25 of the 56 specimens were successful in growing tumor in our immunodeficient mice. The frequency of success based on the type and site of tissue harvest may be seen in Table 1. We found biopsy tissue to be significantly more successful compared to surgical tissue, 61.9% compared to 34.2% (p-value=0.044). Conclusions: We believe our xenograft model, using biopsy tissue, demonstrates the feasibility of a real time personalized in vivo model to aid in the selection of targeted treatments for systemic therapy in ccRCC patients. [Table: see text]

scholarly journals S-Allylmercaptocysteine induces G2/M phase arrest and apoptosis via ROS-mediated p38 and JNK signaling pathway in human colon cancer cells in vitro and in vivo

RSC Advances ◽  
2017 ◽  
Vol 7 (77) ◽  
pp. 49151-49158 ◽  
Author(s):  
Xiaosong Zhu ◽  
Xiaoyan Jiang ◽  
Chonggang Duan ◽  
Ang Li ◽  
Yueyue Sun ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Human Colon ◽  
Cancer Cell Growth ◽  
Human Colon Cancer ◽  
M Phase ◽  
Jnk Signaling Pathway ◽  
Human Colon Cancer Cells ◽  
Dependent Pathway

SAMC inhibits colon cancer cell growth through the reactive oxygen species-dependent pathway.

scholarly journals Indole hydrazide compound ZJQ-24 inhibits angiogenesis and induces apoptosis cell death through abrogation of AKT/mTOR pathway in hepatocellular carcinoma

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Jing Liu ◽  
Ying Liu ◽  
Jianqiang Zhang ◽  
Dan Liu ◽  
Yafeng Bao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Scientific Evidence ◽  
Flow Cytometric Analysis ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Flow Cytometric ◽  
M Phase

Abstract Angiogenesis and the activation of AKT/mTOR pathway are crucial for hepatocarcinoma development and progression, the activation of mTORC1/2 and relevant substrates have been confirmed in clinical hepatocarcinoma samples. Therefore, AKT/mTOR pathway represents the major targets for anti-cancer drugs development. Here, we investigated the anti-proliferative activity and mechanisms of ZJQ-24 in hepatocellular carcinoma, both in vivo and in vitro. A hepatocellular carcinoma xenograft model showed that ZJQ-24 significantly inhibited tumor growth with few side effects. MTT assays, flow cytometric analysis, Western blotting and immunohistochemistry identified that ZJQ-24 effectively suppressed hepatocellular carcinoma cell proliferation via G2/M phase arrest and caspase-dependent apoptosis but had no cytotoxic on normal cells. Furthermore, ZJQ-24 significantly blocked AKT/mTOR signaling by down-regulation of mTORC1 molecules, including phospho-p70S6K (Thr389) and phospho-4EBP-1 (Ser65, Thr37/46, Thr70) and phospho-AKT (Ser473) in HCC cells. It is very important that the ZJQ-24 did not induce the mTORC1-depdent PI3K/Akt feedback activation through JNK excitation. Moreover, ZJQ-24 inhibited the cap-dependent translation initiation by impairing the assembly of the eIF4E/eIF4G complex. Immunohistochemistry further confirmed ZJQ-24 inhibited the tumor growth through suppression of VEGF and AKT/mTOR pathways in vivo. Thus, the present study is the first to illustrate that ZJQ-24 triggers antiangiogenic activity and apoptosis via inhibiting the AKT/mTOR pathway in hepatocellular carcinoma cells, providing basic scientific evidence that ZJQ-24 shows great potential function as inhibitor of angiogenesis and tumor growth in hepatocellular carcinoma.

scholarly journals LMD-07. In Vitro AND In Vivo Culture of Patient Derived-Cerebral Spinal Fluid-Circulating Tumor Cells (PD-CSF-CTCs) in Leptomeningeal Disease (LMD) From Melanoma to Identify Novel Treatment Strategies

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii8-iii8
Author(s):  
Vincent Law ◽  
Zhihua Chen ◽  
Inna Smalley ◽  
Francesca Vena ◽  
Robert Macaulay ◽  
...  
Keyword(s):  
Cell Line ◽  
Treatment Strategies ◽  
Xenograft Model ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
P Value ◽  
Leptomeningeal Disease ◽  
In Vivo Culture

Abstract Background Approximately 5% of melanoma patients (pts) will develop LMD. Currently there is no effective treatments for this disease. A significant barrier to the development of effective therapies has been the inability to culture CSF-CTCs for functional analysis. For the first time, we were able to successfully expand CSF-CTCs in vitro and in vivo. We assessed gene signatures of PD-CSF-CTCs to determine novel targets for therapy. As a proof of concept, we tested the efficacy of combining ceritinib (cer), an IGF-1R inhibitor and trametinib (tra), a MEK inhibitor, against LMD. Methods CSF from 11 pts were collected from various sources (ie: LPs, Ommayas, rapid autopsies). PD-CSF-CTCs were expanded in vitro in conditioned media and in vivo using cell line-derived xenograft model. Single-cell RNA-sequencing (scRNAseq) analysis was performed to assess transcriptional profiles of PD-CSF-CTCs. Results Of the total 61 PD-CSF-CTCs collected from 11 pts (avg: 4.07 CSF collections/patient), we successfully cultured PD-CSF-CTCs from 3 pts (20%) and were able to grow them in vivo from 2 pts (18%). scRNAseq identified IGF-1R, Sox9, ErbB3 and MLANA were among the enriched genes for PD-CSF-CTCs. IGF-1R inhibition by cer and depletion by CRISPR suppressed cell growth. We evaluated the responses of cer + tra treatment in vitro and found that combining these agents produced drug synergy against PD-CSF-CTCs and resensitized BRAF inhibitor-resistant melanoma cell line, WM164R. In vivo LMD xenograft model showed cer + tra treatment significantly prolonged median survival of PD-CSF-CTCs LMD (control: 27 days vs treatment: 38.5 days; P value < 0.032) and WM164R LMD (control: 35 days vs treatment: MS not reached; P value < 0.047). Conclusions Though the sample size is small, this is the first report of the successful in vitro and in vivo culture of CSF-CTCs from pts with LMD.

scholarly journals Chinese Herbal Medicine Ganoderma tsugae Displays Potential Anti-Cancer Efficacy on Metastatic Prostate Cancer Cells

2019 ◽  
Vol 20 (18) ◽  
pp. 4418 ◽  
Author(s):  
Wen-Chin Huang ◽  
Meng-Shiun Chang ◽  
Shih-Yin Huang ◽  
Ching-Ju Tsai ◽  
Pin-Hung Kuo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Xenograft Model ◽  
Ethanol Extract ◽  
Cancer Cell Growth ◽  
Medicine Quality

Resistance to the current therapies is the main clinical challenge in the treatment of lethal metastatic prostate cancer (mPCa). Developing novel therapeutic approaches with effective regimes and minimal side effects for this fatal disease remain a priority in prostate cancer study. In the present study, we demonstrated that a traditional Chinese medicine, quality-assured Ganoderma tsugae ethanol extract (GTEE), significantly suppressed cell growth and metastatic capability and caused cell cycle arrest through decreasing expression of cyclins in mPCa cells, PC-3 and DU145 cells. GTEE also induced caspase-dependent apoptosis in mPCa cells. We further showed the potent therapeutic efficacy of GTEE by inhibiting subcutaneous PC-3 tumor growth in a xenograft model. The in vitro and in vivo efficacies on mPCa cells were due to blockade of the PI3K/Akt and MAPK/ERK signaling pathways associated with cancer cell growth, survival and apoptosis. These preclinical data provide the molecular basis for a new potential therapeutic approach toward the treatment of lethal prostate cancer progression.

scholarly journals Mutant-selective degradation by BRAF-targeting PROTACs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shanique Alabi ◽  
Saul Jaime-Figueroa ◽  
Zhan Yao ◽  
Yijun Gao ◽  
John Hines ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Xenograft Model ◽  
Braf Inhibitor ◽  
Therapeutic Window ◽  
Missense Mutations ◽  
Cancer Cell Growth ◽  
Selective Degradation ◽  
Approved Drugs ◽  
Mutant Braf

AbstractOver 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low  nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window.

scholarly journals Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo Zhou ◽  
Meng Xia ◽  
Bin Wang ◽  
Niresh Thapa ◽  
Lijuan Gan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Annexin V ◽  
Therapy Resistance ◽  
Tumor Xenograft ◽  
Cancer Cell Growth ◽  
Cisplatin Therapy

Abstract Background Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo. Results We performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone. Conclusion Collectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

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