Category: Clinical Trials

Weill Cornell Researcher: A Personalized Approach for Targeting Cancer Tumors

Through a collaboration between researchers at Weill Cornell Medical College, Memorial Sloan-Kettering, and the National Cancer Institute, researchers have reported that a tumor-targeting compound called PU-H71 can reveal with great accuracy the set of altered pathways that contribute to malignancy, thus allowing physicians to “fish-out” entire networks of abnormal proteins in tumor cells.

One major obstacle in the fight against cancer is that anticancer drugs often affect normal cells in addition to tumor cells, resulting in significant side effects. Yet research into development of less harmful treatments geared toward the targeting of specific cancer-causing mechanisms is hampered by lack of knowledge of the molecular pathways that drive cancers in individual patients.

“A major goal of cancer research is to replace chemotherapy with drugs that correct specific molecular pathways disrupted by cancer,” said Weill Cornell’s  Dr. Ari Melnick, one of the study’s lead investigator. The research was published in Nature Chemical Biology.

The researchers have uncovered that PU-H71 can reveal, with great accuracy, the set of altered pathways contributing to malignancy, thus allowing physicians to “fish-out” entire networks of abnormal proteins in tumor cells. PU-H71 binds to these abnormal protein complexes which are part of protein networks supporting cancer cell growth, division and survival. This knowledge could lead to more targeted, effective and individualized therapies for the personalized treatment of cancer – a disease in which no two tumors are alike – while producing fewer side effects and ultimately sparing patients from undergoing chemotherapy.

Based on these findings Dr. Melnick and colleagues have received a multi-investigator collaborative grant from the National Cancer Institute in support of clinical trials for the treatment of cancer. Currently, patients are being recruited for the first clinical trial to test the safety of PU-H71 as a drug used for the treatment of a variety of tumors. Subsequent trials will include patients with cancers such as breast, lymphomas, and chemotherapy-resistant leukemia.

PYRAMID: A Personalized Medicine Study in Lymphoma

Update: this study is closed to enrollment. 

Pyramid Trial Background

With increasing knowledge of cancer biology and availability of new drugs, it is expected that therapy will be increasingly tailored to individual patients’ tumor subtypes. Examples of this in breast cancer, colon cancer and CML have emerged over the past ten years. Often referred to as “personalized medicine” or “precision medicine”, this targeted approach to cancer therapy relies on translational research that defines a drug’s clinical activity in the context of the tumor’s cellular and genomic pathology.

Translational research has characterized the molecular basis of the clinical heterogeneity in various lymphomas, and many new agents are in development for lymphoma. Although the targeted development of these drugs in specific lymphoma patient subgroups could potentially speed their availability to the right patients, there are two major challenges to targeted trials in lymphoma. First, the empiric clinical research has led to highly active drug combinations that improve outcomes for many patients with lymphoma and in some specific types current therapy does in fact successfully treat a portion of the patients; leaving fewer patients with an unmet medical need to enter clinical trials. Second, it is a practical challenge to test and quickly identify specific lymphoma patient subgroups that can be enrolled in clinical trials of targeted drugs. Therefore a personalized study should ideally use a practical, rapid test to identify a lymphoma group that is not responsive to known treatment and test a therapy that targets an important pathway in those tumors.

Pyramid Trial Summary

The PYRAMID trial addresses both of these issues in order to test an investigational combination of R-CHOP with or without VELCADE, a known NFKB inhibitor, specifically in non-GCB lymphoma. Continue reading “PYRAMID: A Personalized Medicine Study in Lymphoma”

Lymphoma in the News: Two Important Studies Take Us One Step Closer to Personalized Lymphoma Therapy

By Peter Martin, MD and Olivier Elemento, PhD

Based on multiple randomized phase 3 studies initiated over a decade ago, R-CHOP chemotherapy is the standard of care for first-line treatment of patients with diffuse large B-cell lymphoma (DLBCL). However, sometimes R-CHOP is not successful. Fortunately, our understanding of lymphoma has evolved over the past decade.

It is increasingly clear that “DLBCL” is a heterogeneous group of related tumors. Studies using gene expression profiling [1], have revealed that DLBCL can be divided into three subgroups based on the probable cell of origin (i.e., the cell from which the lymphoma was derived): activated B-cell like DLBCL (ABC), germinal center-like DLBCL (GCB), and a third group, termed “type 3”, that doesn’t possess any specific characteristics (click here to read the abstract). So far, the clinical relevance of differentiating between the ABC and GCB subtypes of DLBCL remains somewhat unclear. Nonetheless, studies done at Weill Cornell Medical College and elsewhere have suggested that certain treatments might preferentially benefit one subtype (see here and here). As a result, ongoing clinical trials are evaluating newer therapies targeted to the appropriate subgroup.

Just as we are beginning to understand the significance of DLBCL gene expression profiles, recent technological advances in DNA sequencing are making the rapid, high-resolution sequencing of a tumor’s entire genome (DNA code) possible and affordable [2]. Two recently published papers describe the results of long-term efforts by two different groups to sequence the genome of DLBCL tumors.

A Groundbreaking Study

In a paper entitled “Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma” published in the journal Nature, Gascoyne, Marra and colleagues describe the results of a groundbreaking study. The researchers sequenced the entire DNA code from lymphoma tumors and compared the results to normal DNA obtained from the same patients. They were able to identify several genes that were mutated in the tumors but not in the normal DNA. Using these data, they were able to identify 109 genes with a potential role in lymphoma. Continue reading “Lymphoma in the News: Two Important Studies Take Us One Step Closer to Personalized Lymphoma Therapy”