Meta-Analysis of Safety Effectiveness Profile and Overall Response Rate of Metastatic Renal Cell Carcinoma Treatments

Class of 2019 AbstractSpecific Aims: The aim of this project was to determine the overall efficacy of metastatic renal cell carcinoma pharmacotherapeutic agents as well as determine which chemotherapeutic treatment had the lowest side effect profile. Methods: Overall, a MESH database search was done in PubMed that pulled relative clinical trials that examined chemotherapeutic medications for metastatic renal cell carcinoma. From there the papers were analyzed based on particular demographics such as: Drug Treatment, Drug Comparator, Overall Survival, Progression Free Survival, and Overall Response Rate. This was done through a fixed effects analysis comparing the odds ratios for the different mediations. A network diagram was also developed to show the relationship of the studies. Data was then further analyzed for overall side effect profiles which looked at the total number of adverse events in a study. Main Results: The main result is that Nivolumab + Ipilimumab has the lowest Odds Ratio OR = 0.08 ( 0.03 – 0.21, 95% CI) when compared to Lenvatinib. This is in terms of overall response. With regards to the side effect profiles of the medications, Nivolumab vs Everolimus produced the lowest side effect profile with roughly 27%. Conclusions Nivolumab appears to be the medication that has the greatest overall response rate and least adverse side effect profile. This also depends if the medication is combined with Ipilimumab for greater overall treatment response.This item is part of the Pharmacy Student Research Projects collection, made available by the College of Pharmacy and the University Libraries at the University of Arizona. For more information about items in this collection, please contact Jennifer Martin, Librarian and Clinical Instructor, Pharmacy Practice and Science, [email protected]

pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1).

Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr(421)) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr(421)-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr(421)-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr(421)-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr(421)-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr(421)-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr(421)-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr(421)-CTTN expression

The biological role of Treg cells in ectopic endometrium homeostasis

Although retrograde menstruation is observed in up to 90% of women, endometriosis actually develops in only15% of women. There is considerable evidence in the literature that ectopic endometrial cells are able to evade immune surveillance and that the immune response in the microenvironment of ectopic lesions is limited. Endometriosis develops when a deficiency in the local immune response has been generated, and progression of the disease is related to the intensity of this process. Over the last couple of decades it has been well known that T regulatory lymphocytes (Tregs) play a crucial role in controlling a variety of physiological and pathological immune responses. In this review we have focused on the physiological alteration of Treg cell infiltration into the endometrium during the reproductive processes of women. We discuss how a disturbance in Treg cell expansion is involved in generating such pathological processes as miscarriage and ectopic pregnancy development. We hypothesize about the role Treg cells might play in the survival of endometriosis foci in ectopic localization and in the evasion of such lesions from host immune surveillance

The biological role of Treg cells in ectopic endometrium homeostasis

Although retrograde menstruation is observed in up to 90% of women, endometriosis actually develops in only15% of women. There is considerable evidence in the literature that ectopic endometrial cells are able to evade immune surveillance and that the immune response in the microenvironment of ectopic lesions is limited. Endometriosis develops when a deficiency in the local immune response has been generated, and progression of the disease is related to the intensity of this process. Over the last couple of decades it has been well known that T regulatory lymphocytes (Tregs) play a crucial role in controlling a variety of physiological and pathological immune responses. In this review we have focused on the physiological alteration of Treg cell infiltration into the endometrium during the reproductive processes of women. We discuss how a disturbance in Treg cell expansion is involved in generating such pathological processes as miscarriage and ectopic pregnancy development. We hypothesize about the role Treg cells might play in the survival of endometriosis foci in ectopic localization and in the evasion of such lesions from host immune surveillance

Curcumin physically interacts with PTPN1.

<p>(<b>A</b>) Synthesis of biotinylated curcumin derivative. (<b>B</b>) Comparison of the effects of unmodified curcumin (CUR) and biotinylated curcumin (BIO-CUR) in equimolar concentrations (50 µM) on pTyr⁴²¹-CTTN in HCT116 cells treated for 15 min. GAPDH served as a loading control. (<b>C</b>) Western blot analysis (left panel) and quantitative densitometry of the PTPN1 protein from pull-down experiment with biotinylated crcumin. HCT116 cell lysates were prepared with RIPA buffer and combined with curcumin (CUR), biotin linker (compound 3), or biotinylated curcumin (BIO-CUR; compound 4; all at 50 µM) for 30 min at room temperature. Protein fraction recovered with streptavidin agarose beads was analyzed by western blotting for the presence of PTPN1. The data in the summary graph are expressed as fold change compared to linker treated samples from more extended exposures to visualize background PTPN1 signal (mean ± SD). * p<0.05 linker vs. biotinylated curcumin; Student's T-test. All images representative of three independent experiments.</p

Expression of cortactin in human colon adenocarcinomas samples.

<p>(<b>A</b>) Total RNA was extracted from frozen samples of normal and tumor tissues and cortactin mRNA expression was determined using quantitative RT-PCR. The box plots depict relative quantities of cortactin normalized to GAPDH in normal and tumor tissues (n = 37 for normal samples, n = 44 for tumor samples). (<b>B</b>) DNA gel analysis of PCR products obtained from qPCR analysis (representative of 37 normal tissues, 5 benign tumors, and 39 malignant tumors). (<b>C</b>) The tissue lysates of matched pairs (N-normal, M-malignant) of colon specimens prepared from the same tumor samples as in (A) were analyzed the expression of pTyr⁴²¹-cortactin (pTyr⁴²¹-CTTN) and total cortactin by Western blotting. Representative results are shown from three matched pairs. β-actin was used as a loading control. (<b>D</b>) Representative pTyr⁴²¹-cortactin and total cortactin immunostaining of colon tumor specimens. Tissue array containing a series of colon carcinomas were stained for pTyr⁴²¹-CTTN and total cortactin. The staining was mostly cytoplasmic for total cortactin, whereas pTyr⁴²¹-CTTN showing increased staining intensity at the plasma membrane.</p

Overexpression of cortactin promotes migration in colon cancer cells; inhibition by curcumin.

<p>Ectopic expression of cortactin was accomplished by adenoviral delivery (Ad-CTTN) and elevated expression confirmed by qRT-PCR (<b>A</b>) and western blotting (<b>B</b>). (<b>C</b>) Enhanced migration of HCT116, SW480, and HT29 cells transduced with Ad-CTTN. (<b>D</b>) HCT116, and SW480, but not HT29 cells treated with curcumin showed significantly reduced migration. * p<0.05 Control vs. Ad-CTTN or Control vs. Curcumin; Student's T-test. n.s. – not statistically significant. Bars represent mean ± SEM of three independent experiments.</p

Identification of cortactin as curcumin target in colon cancer cells.

<p>(<b>A</b>) Table with 13 plasma membrane-associated proteins identified by QTOF-MS/MS as significantly decreased in T84 cell monolayers treated with curcumin. Data shows average number unique peptides identified from three different experiments ± SD. (<b>B</b>) Quantitative analysis of cortactin expression in the T84 cells by M/S. The spectrum values were obtained from three different experiments. The quantification data for cortactin protein was derived from M/S using Scaffold proteome software (version Scaffold_3.1.2). Data are means ± SE, *<i>p</i><0.05 compared with untreated cells, Student's t test. (<b>C</b>) Confirmation of CTTN protein expression by western blotting with biotinylated cell surface protein fraction prepared from T84 cells treated with DMSO (CTRL) or 50 µM curcumin for 1–4 hours. CD71 (transferrin receptor) was used as a loading control. CTRL represents cells treated with DMSO for 4 hours.</p

Curcumin impairs the physical interaction between cortactin and p120 catenin (CTNND1).

<p>HCT116 cells were treated with 50 µM curcumin for 15 min and pre-cleared lysates were immunoprecipitated using anti- pTyr⁴²¹-CTTN or anti-CTTN (total) rabbit polyclonal antibodies. Immunoprecipitated complexes were analyzed by Western blotting for the presence of CTNND1. Lower three panels demonstrate even input of CTTN, CTNND1 and GAPDH in the cell lysates used for co-immunoprecipitation. All images representative of three independent experiments.</p