SNPMiner Trials by Shray Alag

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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation T47D

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 3 clinical trials

Clinical Trials


1 Randomised Control Cross-over Trial to Test How Dietary Plant Sterols Modify Tumour Promoting Capabilities of Non-tumour Host Cells in Volunteers With Elevated LDL-C

Several types of human cells convert cholesterol into other molecules, including oxysterols. Oxysterols can promote breast cancer growth and help tumours to spread. Some breast cancer types recruit other cells (host cells) able to produce oxysterols within the local cancer environment. How these other cells help breast tumours metastasize or resist chemotherapy is not well understood, but epidemiological and clinical studies suggest elevated LDL-C is associated with worse survival, poorer response to therapy and an increased propensity for disease relapse in breast cancer patients. In this trial the investigators will test how an LDL-C lowering dietary intervention (using commercially available phytosterol added food products), alters the ability of non-cancer cells (adipocytes, fibroblasts and macrophages) collected from high LDL-C volunteers to change chemotherapy response and metastatic process in breast cancer cells. In this trial, volunteers with high LDL-C levels will be recruited by the University of Leeds, and divided randomly into two arms that cross over. The experimental period (yogurt drink enriched with phytosterols) and placebo period (non-enriched yogurt drink) will each last for 8 weeks, alternated with a 4 weeks of wash-out period. Samples will be collected 4 times (week-0, week-8, week-12, week-20) during the study and will include blood, white blood cells (macrophages), and fat tissue cells. Measurements will include oxysterol, LDL-C and phytosterol concentrations (volunteers' serum/plasma, media from the host cells/breast cancer experimental culture) and how the host cells alter the behaviour of cancer cells in the laboratory.

NCT04147767
Conditions
  1. Hypercholesterolemia
  2. Breast Cancer
  3. Obesi
  4. Obesity
Interventions
  1. Dietary Supplement: Cholesterol Reducing Strawberry Yogurt Drink (Tesco Ltd)
  2. Dietary Supplement: Low Fat Strawberry Yogurt Drinks (Morrisons Ltd)
MeSH:Hypercholesterolemia
HPO:Hypercholesterolemia

MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial.. Study of adipocytes and macrophages interaction with breast cancer cell lines. --- T47D ---

MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial. --- T47D ---

Primary Outcomes

Description: The changes of oxysterols content in serum/plasma after 8 weeks of phytosterols intervention compared to placebo. After the dietary intervention, we expect to observe a change of -20% in circulating 27-hydroxycholesterol content (marker of oxysterols systemic levels). Concentration of oxysterols using LC-MS/MS measurement of plasma in 50 subjects after placebo and after intervention.

Measure: To change circulating oxysterols levels after phytosterols intervention.

Time: Serum/plasma oxysterols concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Secondary Outcomes

Description: Concentration of oxysterols using LC-MS/MS measurement of host cells in 50 subjects after placebo and after intervention. Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial.

Measure: Change intra-cellular adipocyte and macrophages oxysterols concentrations

Time: Serum/plasma/medium oxysterols concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial. Changes in proteins expression of oxysterols target genes.

Measure: Study of adipocytes and macrophages interaction with breast cancer cell lines

Time: Protein expression will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial. Changes in gene expression of oxysterols target genes.

Measure: Study of adipocytes and macrophages interaction with breast cancer cell lines

Time: Gene expression will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Study of the effect of phytosterols on LDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Measure: Study the effect of phytosterols on LDL-C

Time: Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Study of the effect of phytosterols on HDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Measure: Study the effect of phytosterols on HDL-C

Time: Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Study of the effect of phytosterols on Total Cholesterol concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Measure: Study the effect of phytosterols on Total Cholesterol

Time: Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Study of the effect of phytosterols on Triglycerides concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Measure: Study the effect of phytosterols on Triglycerides

Time: Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Study of the effect of phytosterols on non-HDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Measure: Study the effect of phytosterols on non-HDL-C

Time: Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Phytosterols panel serum/plasma levels after phytosterols enriched food or placebo intervention during all the steps of the trial.

Measure: Quantify phytosterols in blood samples from volunteers.

Time: Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Other Outcomes

Description: RNA sequence will be measured with RNA-seq techniques before and after phytosterols intervention to identify the molecular effectors of the paracrine regulatory systems in the oxysterols, LDL-C and secondary BCa pattern.

Measure: Study RNA sequences changes in the oxysterols/LDL-C pathway and secondary breast cancer before and after phytosterols intervention .

Time: RNA will be studied during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

Description: Changes in interactions between proteins and DNA and using Chip/seq will be measured before and after phytosterols intervention to identify the molecular effectors of the paracrine regulatory systems in the oxysterols, LDL-C and secondary BCa pattern.

Measure: Study changes in the interactions between proteins and DNA in the oxysterols/LDL-C pathway and secondary breast cancer before and after phytosterols intervention .

Time: interactions between proteins and DNA will be studied during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)

2 Mifepristone Treatment for Breast Cancer Patients Expressing Levels of Progesterone Receptor Isoform A (PRA) Higher Than Those of Isoform B (PRB): Neoadjuvant Therapy.

- Seventy per cent of breast cancers express estrogen (ER) and progesterone receptors (PR) and respond to endocrine treatment. - Actual therapy targets ER. - There is enough evidence that progestins participate regulating breast cancer growth. - Antiprogestins block cell proliferation and increase apoptosis in breast cancer models which express high levels of PRA. - Antiprogestins have been used to treat breast cancer patients that failed to other treatments; benefits were seen in selected patients. - Mifepristone (MFP) is currently used for medical abortion and for the treatment of Cushing disease. - MFP might exert agonistic effects when PRB isoform is activated by cAMP. This makes mandatory the evaluation of the PR isoform ratio in breast cancer patients in which MFP is a therapeutic possibility. Main Goal To evaluate if therapeutic doses of MFP exert beneficial effects on breast cancers expressing levels of PRA higher than those of PRB, evaluated as an inhibition in proliferation markers and/or an increase in apoptotic markers. - Eligibility - Postmenopausal women (one year after menses stop). - Women with tumors showing ratios of PRA/PRB higher than 1.5 and PR higher than 50%. - Women without previous treatment. - All clinical stages with tumors larger than 1.5 cm. - Patients without autoimmune diseases and/or asthma. - Study design - Open Interventional. - Twenty women will take MFP (200 mg) p.o. once /day during 14 days. As for preliminary studies, to reach this number the investigators will have to evaluate 80-100 patients. - Surgery is performed 14 days after treatment initiation, 24 hs after last dose. - PR isoform ratio will be evaluated by western blots (WB) in one core biopsy. Additional cores will be used for diagnosis, immunohistochemistry (IHC) of PR, Ki-67 and other markers. - At surgery samples will be frozen for molecular studies and fixed and processed for pathological evaluation. - Wilcoxon signed rank test will be used to evaluate differences in biomarker expression between core biopsy and surgical samples of each patient. - Blood will be collected before treatment initiation and prior to final surgery. - Mammographic and echographic studies will be carried out before and after treatment.

NCT02651844
Conditions
  1. Breast Cancer
Interventions
  1. Drug: Mifepristone
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

T47D cells will be used as a positive control. --- T47D ---

Primary Outcomes

Description: Treatment efficacy will be assessed by comparing tissue samples from the baseline biopsy and tissue samples collected from the day of surgery, evaluating if there is a decrease in the proliferating index (Ki-67 expression by immunohistochemistry). Positive response: differences higher than 30%.

Measure: Measurable decrease in tumor cell proliferation from baseline to time of surgery

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Secondary Outcomes

Description: Treatment efficacy will be assessed by comparing tissue samples from the baseline biopsy and tissue samples collected from the day of surgery, evaluating if there is an increase in apoptotic cells measuring TUNNEL and caspase 3 expression. Positive response: difference higher than 30%.

Measure: Measurable increases in apoptotic markers from baseline to time of surgery

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Description: MFP action will be measured evaluating the expression of downstream markers related to PR activation such as CCND1, MYC, pSTAT5 and other proteins by immunohistochemistry. Positive response: differences higher than 30%

Measure: Measurable changes in signaling pathways downstream PR

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Other Outcomes

Description: Measured by ecographic imaging. Twenty per cent of decrease in overall tumor size will be considered as a significant change.

Measure: Changes in tumor size

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Description: Differences in gene expression between biopsy core and surgery sample higher than 20 % will be considered as an effective drug response.

Measure: RNAseq analysis of gene expression

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

Description: Levels of Mifepristone will be measured by HPLC in the blood sample after treatment and correlate these levels with response to treatment (outcome 1).

Measure: Measure serum Mifepristone levels after 14 days Mifepristone treatment

Time: Baseline to time of surgery (14 days of treatment between biopsy core and surgery)

3 A Phase II Window-of-opportunity Study of Single Agent Lenvatinib in Estrogen Receptor Positive Early Stage Breast Cancer

The Investigators hypothesize that single agent lenvatinib has biological activity in estrogen receptor positive breast cancer, and that the effects are more pronounced in patients with positive RET expression in the tumor.

NCT03168074
Conditions
  1. Breast Cancer
Interventions
  1. Drug: lenvatinib
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

The investigators tested 9 ER+ breast cancer cell lines for RET expression using Western blot, and identified 4 with high expression (BT474, MB361, HCC1419, UACC812), 2 with normal expression (MCF7, CAMA1), and 3 with low expression (T47D, ZR-75-1, BT483). --- T47D ---

To evaluate the effects of combining lenvatinib with endocrine therapy in ER+ breast cancer cell lines with different RET expression, the investigators performed experiments using 6 cell lines, including 2 with high RET expression (BT474, MB361), 2 with normal RET expression (MCF7, CAMA1), and 2 with low RET expression (T47D, ZR-75-1). --- T47D ---

Lenvatinib was at least additive with tamoxifen in all 6 ER positive breast cancer cell lines tested, with the combination resulting in ≥50% cell kill compared to single agent tamoxifen in BT474, CAMA1, and T47D cell lines. --- T47D ---

Primary Outcomes

Description: To evaluate Ki67 changes. The Ki-67 protein is a cellular marker for proliferation. It is strictly associated with cell proliferation. Ki67 has been shown to be a surrogate marker of biological activity and treatment response in estrogen receptor positive breast cancer treated with endocrine therapy.

Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design

Time: after 10-28 days of single agent lenvatinib

Description: To evaluate histological response such as the improvement in the appearance of microscopic tissue specimens after treatment with lenvatinib. The improved appearance of biopsy specimens after treatment often suggests the patient's prognosis will improve as well.

Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design

Time: after 10-28 days of single agent lenvatinib

Description: To evaluate apoptosis. Apoptosis is the death of cells which occurs as a normal and controlled part of an organism's growth or development. The presence of apoptosis indicates anti-cancer effects.

Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design

Time: after 10-28 days of single agent lenvatinib

Description: To evaluate RET. RET is an estrogen response gene. RET is associated with resistance to tamoxifen and aromatase inhibitors, and increased RET expression has been demonstrated in hormone resistant cell lines and primary tumors.

Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design

Time: after 10-28 days of single agent lenvatinib

Description: To evaluate downstream targets such as AKT. AKT /protein kinase B (PKB) is a cardinal node in diverse signaling cascades important in both normal cellular physiology and various disease states. AKT signaling regulates cell proliferation and survival, cell growth (size), glucose metabolism, cell motility and angiogenesis. Aberrant regulation of these processes results in cellular perturbations considered hallmarks of cancer, and numerous studies testify to the frequent hyperactivation of AKT signaling in many human cancer.

Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design

Time: after 10-28 days of single agent lenvatinib

Description: To evaluate downstream targets such as ERK. ERK is Extracellular signal-regulated kinase. Deregulation of ERK signalling pathway is linked to many other aspects of the tumour phenotype.

Measure: Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design

Time: after 10-28 days of single agent lenvatinib

Secondary Outcomes

Description: to obtain the percentage change in primary breast tumor dimension measured by ultrasound

Measure: Changes in the primary tumor dimensions

Time: after 10-28 days of single agent lenvatinib

Description: to obtain the proportion of subjects with tumor reduction of at least 10%

Measure: The proportion of subjects with tumor reduction

Time: after 10-28 days of single agent lenvatinib

Description: To compare clinical response of lenvatinib in RET negative versus RET positive, ER positive breast cancers

Measure: Comparison of the clinical response of lenvatinib in RET negative versus RET positive, ER positive breast cancers

Time: after 10-28 days of single agent lenvatinib

Description: : Comparison of the number of patients with Ki67 changes, histological response, apoptosis, RET and downstream targets such as AKT and ERK, between RET negative versus RET positive, ER positive breast cancers.

Measure: Comparison in the overall average changes in biological effects of lenvatinib between RET negative and RET positive, ER positive breast cancers.

Time: after 10-28 days of single agent lenvatinib


HPO Nodes