Tag: Ari Melnick MD

Pretreating DLBCL with Targeted Therapy Improves Patient Outcomes and Chemotherapy Effectivenes

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with high rates of relapse and survival rates that rarely extend beyond two years. However, researchers from the Weill Cornell Lymphoma Program have recently published a study in Cancer Discovery, with the potential to change the standard of care for patients with DLBCL. This study focused on the use of azacitidine (Vidaza), a targeting therapy designed to reawaken the molecular mechanisms that typically trigger cell death but are switched off as lymphoma progresses. Researchers found a resurgence in the death signal on the resumption of chemotherapy for those DLBCL patients treated with azacitidine in advance of chemotherapy. 

As the study’s senior investigator Dr. Leandro Cerchietti, the Raymond and Beverly Sackler Research Scholar and assistant professor of medicine at Weill Cornell Medical College noted, “To have any hope for helping patients with aggressive lymphoma, we need to make this resistant cancer sensitive to treatment. We found we could do this by reprogramming the cancer to a more benign disease, which can then respond to chemotherapy…By pre-treating patients with a low-dose of azacitidine — a targeted drug approved for use in myelodysplastic syndrome — we achieved a profound and stable degree of reprogramming and chemosensitization that was very surprising to us.”

In the proof of concept, phase 3 study led by Dr. Peter Martin, patients received low doses of azacitidine five days in advance of standard chemotherapy. 11 patients achieved a complete remission of cancer, while 10 remained cancer-free for up to 28 months. 

Study collaborator, Dr. Ari Melnick commented, “In this remarkable study, Dr. Cerchietti discovered an important new disease mechanism that causes chemotherapy resistance in aggressive lymphomas, developed a new treatment regimen and completed the first clinical trial, demonstrating that his findings are true and directly relevant to those patients with the most severe forms of this tumor.” 

The implications for this study are far ranging. Dr. Cerchietti explained, “Oncologists have long believed that using high doses of an anti-cancer drug is the best strategy. Our study shows that is not the case in this kind of lymphoma, and suggests this new approach can potentially be translated to other tumor types.”

Researchers plan on expanding the study to additional DLBCL patients in a multi-center clinical trial, while studying pre-treatment strategy options in other tumor types and lymphomas. 

Please look to this space for further updates. A full listings of available clinical trials can be found here. 

Novel Weill Cornell Drug Displays Promise in Treating DLBCL

Following up on an earlier breakthrough confirming the feasibility of shutting down the Bcl6 protein — an important master regulatory transcription factor that is the key to survival for diffuse large-B cell lymphoma and other aggressive B-cell lymphomas– Weill Cornell’s Dr. Ari Melnick and other researchers recently completed a study where five doses of the experimental drug eradicated human lymphoma in mice.

Published online in the journal Cell the researchers described specifically how Bcl6 promotes the survival of DLBCL, before detailing how the Weill Cornell developed Bcl6 inhibitor effectively gums up the protein. Initially developed by Dr. Melnick nine years ago, the interim period has seen him working to improve the design for use by DLBCL and other lymphoma patients, collaborating with other world class researchers to understand how both Bcl6 and its inhibitor functions.

The researchers found that Bcl6 has two independent functions required for the survival of DLBCL. Dr. Melnick described how the first function, “builds a huge shopping mall-style complex”. This complex rests on top of a stretch of the genome. Through this binding Bcl6 deactivates the DNA, prohibiting genes from producing RNA and proteins. As Dr. Melnick noted, “Bcl6 acts like a barcode reader. When it sees that barcode — the DNA sequence — it attaches there”.

He went on, “Normally, the protein complex goes away after an immune reaction has been successfully mounted against the pathogen. But when it doesn’t, and remains stuck to the genes, DLBCL can result. That’s because Bcl6 is inhibiting genes that stop cells from dividing and that sense damage to the genome. We now know the genes that Bcl6 is repressing and how that helps lymphoma develop and survive.”

According to Dr. Melnick the second function, “acts like a switch on railroad track that routes a train in one direction or another. One track is needed when antibodies are required for an immune response, while the other keeps B cells in a constant state of division.”

Importantly the researchers were surprised to find that both the complex and the train switch attach to the Bcl6 protein at the same site. “They fit into the same keyholes on Bcl6,” Dr. Melnick said. “There are two identical binding sites on the protein surface.”

As Dr. Melnick exclaimed, “This is wonderfully serendipitous — our drug just happens to be able to overcome both of the biological mechanisms that are key to survival of aggressive lymphoma,” before adding that the inhibitor completely eradicated DLBCL in mice in a short time, with no detectable side effects.

The team is conducting additional research toward an investigational new drug application from the federal Food and Drug Admission.

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.