New designer compound JQ1, treats heart failure by targeting cell nucleus

Researchers from Case Western Reserve University School of Medicine and the Dana-Farber Cancer Institute have made a fundamental discovery relevant to the understanding and treatment of heart failure -- a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, (see structure)  blocks this pathway to protect the heart from damage.

In contrast to standard therapies for heart failure, JQ1 works directly within the cell's command center, or nucleus, to prevent damaging stress responses. This groundbreaking research lays the foundation for an entirely new way of treating a diseased heart. The study is published in the August 1 issue of Cell.

"As a practicing cardiologist, it is clear that current heart failure drugs fall alarmingly short for countless patients. Our discovery heralds a brand new class of drugs which work within the cell nucleus and offers promise to millions suffering from this common and lethal disease," said Saptarsi Haldar, MD, senior author on the paper, assistant professor of medicine at Case Western Reserve and cardiologist at University Hospitals Case Medical Center.

Heart failure occurs when the organ's pumping capacity cannot meet the body's needs. Existing drugs, most of which block hormones such as adrenaline at the cell's outer surface, have improved patient survival. Unfortunately, several clinical studies have demonstrated that heart failure patients taking these hormone-blocking drugs still succumb to high rates of hospitalization and death. Leveraging a new approach, the research team turned their attention from the cell's periphery to the nucleus -- the very place that unleashes sweeping damage-control responses which, if left unchecked, ultimately destroy the heart.

The team found that a new family of genes, called BET bromodomains, cause heart failure because they drive hyperactive stress responses in the nucleus. Prior research linking BET bromodomains to cancer prompted the laboratory of James Bradner, MD, the paper's senior author and a researcher at the Dana-Farber, to develop a direct-acting BET inhibitor, called JQ1. In models of cancer, JQ1 functions to turn off key cancer-causing genes occasionally prompting cancer cells to "forget" they are cancer. In models of heart failure, JQ1 silences genetic actions causing enlargement of and damage to the heart even in the face of overwhelming stress.

"While it's been known for many years that the nucleus goes awry in heart failure, potential therapeutic targets residing in this part of the cell are often dubbed as 'undruggable' given their lack of pharmacological accessibility," said Jonathan Brown, MD, cardiologist at Brigham and Women's Hospital and co-first author on the paper. "Our work with JQ1 in pre-clinical models shows that this can be achieved successfully and safely."

Ref : http://www.sciencedirect.com/science/article/pii/S0092867413008842

Video : http://www.ted.com/talks/jay_bradner_open_source_cancer_research.html

New designer compound treats heart failure by targeting cell nucleus

Combination of two drugs could be effective strategy to target T-cell lymphocytic leukemia

Researchers have determined that two Phase 1 drugs (CX-4945 and JQ1) can work together to efficiently kill T-cell acute lymphoblastic leukemia cells while having minimal impact on normal blood cells.

 JQ1     CX-4945

Although both drugs were previously tested as single agents in clinical trials to treat cancers, the success of the combined actions on cancer cells was previously unknown until now. The findings appear in the journal Haematologica.

Acute lymphoblastic leukemia, also known as acute lymphocytic leukemia or acute lymphoid leukemia, is a form of cancer of the white blood cells, characterized by the overproduction and accumulation of cancerous, immature white blood cells, known as lymphoblasts. Despite treatment improvement, T-cell leukemia remains fatal in 20 percent of pediatric and 50 percent of adult patients. Both CX-4945 and JQ1 are in clinical trials now as single agents to treat solid and hematological cancers.

"Previous studies provided us a rationale to test the combination of CX-4945 and JQ1 on refractory/relapsed T-cell leukemia," said corresponding author Hui Feng, MD, PhD, assistant professor of pharmacology & experimental therapeutics at Boston University School of Medicine (BUSM). "Our findings suggest that the combination treatment of CX-4945 and JQ1 could be an effective strategy to target refractory/relapsed T-cell leukemia," she added.

According to the researchers the efficacy of using a combination of JQ1 and CX-4945 in treating other cancers should also be investigated.

Ref : http://www.haematologica.org/content/early/2016/10/03/haematol.2016.154013

Novel combination of cancer drugs can have therapeutic impact on diffuse large B-cell lymphoma

In continuation of my update on carfilzomib, JQ1 and ABT 199

New research from Roswell Park Cancer Institute (RPCI) shows that promising cancer drugs used in combination can have significant therapeutic impact on a particularly aggressive subtype of diffuse large B-cell lymphoma (DH-DLBCL) in preclinical studies. The researchers will present their findings at the American Association for Cancer Research (AACR) Annual Meeting 2016, to be held April 16-20 in New Orleans.

Priyank Patel, MD, a fellow in the Department of Medicine at Roswell Park, is the first author and Francisco Hernandez-Ilizaliturri, MD, Clinical Chief of the Institute's Lymphoma/Myeloma Service, is the senior author of "Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL)" (abstract 3038), which will be presented on Tuesday, April 19, at 8 a.m. CDT.

Diffuse large B-cell lymphoma, the most common type of non-Hodgkin lymphoma, is an aggressive form of lymphoma. This research team reviewed a database of 650 patients with diffuse large B-cell lymphoma, identifying 36 patients whose tumors had two or more aberrant genes. Patients with mutations of the c-MYC, BCL2 and/or BCL6 genes — a subtype known as "double-hit lymphoma" — have especially have poor outcomes when treated with standard chemotherapy. The scientists evaluated the effectiveness of three novel anticancer drug candidates that targeted those proteins. In preclinical studies, the therapeutic agents ABT-199, JQ-1 and carfilzomib induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed when researchers combined ABT199 with carfilzomib and, to a lesser extent, with JQ1 in cancer cell lines.

"Increasing knowledge of genetics and molecular pathways has helped us identify a subgroup of patients who harbor aggressive aberrant gene mutations. Understanding the mechanisms of action and clarifying how these potential therapies work to inhibit cancer cell growth may result in improved outcomes for patients diagnosed with this aggressive type of lymphoma," says Dr. Hernandez-Ilizaliturri.

 Carfilzomib   JQ1  ABT-199

Novel combination of cancer drugs can have therapeutic impact on diffuse large B-cell lymphoma: New research from Roswell Park Cancer Institute shows that promising cancer drugs used in combination can have significant therapeutic impact on a particularly aggressive subtype of diffuse large B-cell lymphoma (DH-DLBCL) in preclinical studies. The researchers will present their findings at the American Association for Cancer Research (AACR) Annual Meeting 2016, to be held April 16-20 in New Orleans.

New combination therapy holds promise for treating HER2-positive breast cancer

Resistance to therapy is a major problem in the cancer field. Even when a treatment initially works, the tumors often find ways around the therapy. Using human cell lines of the HER2-positive breast cancer subtype, researchers from the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center have detailed the surprising ways in which resistance manifests and how to defeat it before it happens.

The discovery, published today in the journal CELL Reports, provides the experimental evidence for the potential development of a novel combination therapy for HER2-positive breast cancer. The combination includes the FDA approved drug lapatinib (right structure) and a new experimental drug called a BET bromodomain inhibitor -JQ1 (see structure left), which works by disrupting the expression of specific genes.

 

This study, a collaboration of 20 University of North Carolina researchers, is the first time a BET bromodomain inhibitor has been shown to prevent the onset of resistance to drugs such as lapatinib in breast cancer cells.

"This research was done in cell lines of human HER2-positive breast cancer, not in patients; but the results are very striking," said Gary Johnson, PhD, Kenan Distinguished Professor and chair of the department of pharmacology, member of the UNC Lineberger Comprehensive Cancer Center, and senior author of the paper. "The combination treatments are currently being tested in different mouse models of breast cancer. Our goal is to create a new kind of therapy that could help oncologists make the response to treatment more durable and lasting for breast cancer patients."

Ref : http://www.nature.com/nature/journal/v468/n7327/abs/nature09504.html

New combination therapy holds promise for treating HER2-positive breast cancer