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Tumor Proteins may lead to Targeted Treatment

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    Posted: Mar 30 2017 at 8:03am

Rogue breast tumor proteins point to potential drug therapies

For patients with difficult-to-treat cancers, doctors increasingly rely on genomic testing of tumors to identify errors in the DNA that indicate a tumor can be targeted by existing therapies. But this approach overlooks another potential marker — rogue proteins — that may be driving cancer cells and also could be targeted with existing treatments.

If DNA can be described as the body’s genetic blueprint, proteins can be thought of as the construction workers who carry out the plan. Studying the blueprint can be vital to understanding genetic diseases, including cancer, but that focus also means that some problems arising with the workers may be missed.

Studying mice with breast tumors transplanted from patients, researchers at Washington University School of Medicine in St. Louis, The Broad Institute of MIT and Harvard, and Baylor College of Medicine have analyzed the proteins present in these tumors. The researchers demonstrated that some protein alterations can be used to identify drugs that may work against some cancers. The work is part of the National Cancer Institute’s (NCI) Clinical Proteomic Tumor Analysis Consortium efforts.

The study is published March 28 in Nature Communications.

“Proteins carry out most of the biological functions in the cell,” said senior author Li Ding, PhD, an associate professor of medicine at Washington University. “Knowing the DNA sequence does not automatically tell us everything about the proteins doing work in the cells. This is another layer of tumor complexity that we need to explore to identify new therapies.”

Ding said recent advances in a technology called mass spectrometry and in techniques to analyze massive quantities of data have made complex studies of the proteins in tumor cells possible. Another reason to prioritize the systematic study of proteins in tumors — cancer proteomics — is that the vast majority of cancer therapies developed from genetic studies actually target proteins.

“Identifying the rogue proteins of cancer is an important pathway toward developing new drugs,” said co-author R. Reid Townsend, MD, PhD, a professor of medicine and director of the Proteomics Shared Resource at Washington University.

“We can use proteomics to confirm and validate our genomics findings,” said Ding, also an assistant director of The McDonnell Genome Institute at Washington University School of Medicine. “In addition, it’s another tool to uncover additional events that drive cancer and are specific to individual patient tumors, including the amount of the ‘rogue’ protein, its specific form, or the type and extent of chemical modifications of the proteins that we know are treatable with approved or investigational drugs. We also can test these therapies in the mice before we evaluate them in patients.”

Steven A. Carr, PhD, of the Broad Institute, said the team analyzed a chemical modification called phosphorylation, which plays a central role in how healthy, as well as diseased, cells communicate.

“Disruption or enhancement in such signaling is often directly related to disease mechanism and can be targeted for therapy,” Carr said.

The researchers studied 24 tumor samples from breast cancer patients after the samples were transplanted into mice. Twenty-two of the transplanted samples retained their genetic and proteomic identities as specific types of breast cancer. A proteomic analysis of the tumors also identified multiple protein targets that have the potential to respond to drugs.

For example, the researchers showed dialed-up activity of multiple protein pathways that could be targeted with investigational drugs called PI3K inhibitors and mTOR inhibitors, separately and in combination, depending on the tumor. They also showed that drugs against a type of breast tumor called HER2 positive breast cancer — such as the dual ERBB2/EGFR inhibitor lapatinib — potentially could benefit more patients than currently receive them, if analysis of the tumor proteins is taken into consideration.

While most of these tumor models recapitulated specific types of breast cancer, Ding said the scientists were surprised to see that two of the 24 tumors evolved into a completely different type of cancer after transplantation into the mice. Instead of breast cancer, they resembled lymphoma and were driven by the cancer-causing virus Epstein-Barr, according to the researchers. Lymphomas are cancers of immune cells that may have arisen from lymphatic tissue present in the breast tumors transplanted into the mice.

The analysis of the lymphoma-like cancers was the first proteomic study of this type of tumor. Though unintentional, Ding said the analysis provides an explanation for why investigational drugs that inhibit a protein called BTK have been effective in treating patients with lymphoma.

“Since it is the proteins that interact directly with drugs, the strength of studying proteomics in patient-derived tumor models is the ability to test drug treatment in the mice,” Ding said. “With advances in cancer proteomics that increase the speed of measurement, we are moving toward a future that includes genomic and proteomic analyses of patient tumors.”

Co-author Matthew J. Ellis, MD, PhD, of Baylor, agreed. “The mouse work is promising enough to adapt these technologies for real time analysis of patient materials so that clinical trials can be designed to test this new diagnostic and drug selection approach,” he said.

http://siteman.wustl.edu/rogue-breast-tumor-proteins-point-potential-drug-therapies

DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
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Post Options Post Options   Thanks (0) Thanks(0)   Quote mainsailset Quote  Post ReplyReply Direct Link To This Post Posted: Mar 30 2017 at 12:43pm
Dr Ellis has been busy!
dx 7/08 TN 14x6.5x5.5 cm tumor

3 Lymph nodes involved, Taxol/Sunitab+AC, 5/09 dbl masectomy, path 2mm tumor removed, lymphs all clear, RAD 32 finished 9/11/09. 9/28 CT clear 10/18/10 CT clear
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 31 2017 at 2:46pm
Mainy,

Yes he is!  He was a brilliant, compassionate researcher and oncologist when he was at Siteman and is continuing his groundbreaking work at Baylor.  Beth and I were sad to see him go.  We are so lucky to have people like him trying to unravel the mystery and find mechanisms to halt progression.


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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 10 2018 at 9:02pm

Research shows proteomics can be used to predict evolution of triple negative breast cancer


Researchers from the Spanish National Cancer Research Centre (CNIO) are now publishing in Nature Communications a successful classification of triple breast cancer patients, which for the first time discriminates those who can be cured from those who might suffer a relapse. It also identifies new pharmacological targets, and indicates that in patients with these targets, combined treatments with existing drugs could be effective.

Specifically, they have identified six protein kinases, whose functional status predicts the evolution of triple negative breast cancer. Furthermore, researchers have found a way for these proteins to be studied in hospitals, so that in the future it might be a regular clinical test, just as genetic profile analysis of any tumor is today.

"Until now, it has not been possible to establish a link between the presence of certain mutations in triple negative breast cancer and a prognosis or response to drug treatment", explained oncologist Miguel Ángel Quintela, director of the Breast Cancer Clinical Research Unit at CNIO and lead author on the research paper that is being published now. "We have shown for the first time that proteomics can be used to predict the evolution of triple negative breast cancer, and to select combinations of pairs of drugs as candidates for clinical trials".

From genomics to proteomics

Decades of research into cancer genomics have identified, in many cancers, dominant gene mutations that determine the progression of the tumor and guide the design of personalized treatment pathways. These therapies that target the specific biology of each tumor, more effective than conventional chemotherapy, are largely responsible for the advances made in recent years in cancer treatments.

But triple negative breast cancer is caused by numerous mutations, which act in conjunction and in unique combinations for each patient. So far, it has not been possible to find dominant gene mutations that provide an indicator of prognosis or response to drug treatment.

As the researchers explain in Nature Communications, "although studies based on genetics have provided unprecedented knowledge about breast cancer and its subtypes, in triple negative breast cancer, this new information has revealed major heterogeneity that has prevented us, so far, from defining prognostic or predictive factors. [This fact] has meant that conventional chemotherapy is still the main therapeutic option in triple negative breast cancer".

For that reason "it would be extremely interesting" for this type of cancer to have a classification system associated with different therapeutic options, write the authors.

With this aim, CNIO researchers chose not to analyze the genes involved in triple negative breast cancer, but rather their product: the proteins whose synthesis is ordered by those genes. Their hypothesis was that the numerous genetic alterations of patients could translate into recognizable patterns of the functional status - activation or not - of all the tumor's proteins, its proteome.

They were successful. In samples of tumors from 34 patients, the researchers found the biochemical marks of the activation of tumor proteins; they found more than two million, but with the help of sophisticated bioinformatic tools, they detected that, among all these signals, there is a precise combination that is only found in patients who relapse. These proteins are activated through kinases - which are in turn proteins - and so the next step was to find the kinases responsible for that specific pattern.

Finally, the analysis identified the six kinases responsible for the activation pattern characteristic of the proteome of patients who relapse.

Six kinases indicate probable relapse

So, now we know that these six kinases play a key role in triple negative breast cancer. Some of them had been studied previously, but until now "there was no reason to home in on them", explained Quintela.

The validation of their findings with 170 patients confirmed the value of these six kinases as a marker. Patients in whom none of these proteins was activate had a 95% chance of being cured, or at least not suffering a relapse twelve years after treatment. However, if even one of the six kinases was active, the risk of relapse multiplied by ten.

These six kinases can be inhibited using drugs, and there are already drugs in use against some of them. Furthermore, to prove the clinical relevance of their findings, the researchers studied in xenografts, and in xenografts derived from patients - tumors from patients transplanted onto mice - the anti-tumor activity of 15 different combinations of drugs, and related it with the activation profile of the six kinases.

They found combinations that achieved "promising anti-tumor activity", they write in Nature Communications. Specifically, 15 combinations in ten different models - 150 situations - achieved a superior therapeutic effect to the sum total of the therapeutic effects of each drug separately in 99.3% of cases.

Towards a new clinical trial for kinase activation

Analysis of the functional status of proteins cannot currently be conducted as a routine test in hospitals, but the authors have translated the activation patterns of the kinases into indicators of immunohistochemistry, which can be analyzed easily in hospitals. The objective is for the study of the six kinases identified to become in the future a regular clinical test, in the way that the genetic profiling of any tumor is today.

Currently, researchers are focusing on "validating these markers in other stages of diseases, standardizing kinase determinations by way of a diagnostic test, and organizing clinical trials using the therapeutic combinations described in this paper on patients with advanced disease", said Quintela.

http://www.news-medical.net/news/20180829/Research-shows-proteomics-can-be-used-to-predict-evolution-of-triple-negative-breast-cancer.aspx

https://www.cnio.es/ing/publicaciones/cnio-researchers-find-the-first-indicators-of-prognosis-for-the-most-aggressive-type-of-breast-canc





Edited by 123Donna - Sep 10 2018 at 9:02pm
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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