Tag: Jia Ruan MD

New Pre-clinical Research Shows Transcription-Targeting Drug Useful in T-cell Lymphoma

Peripheral T-cell Lymphomas (PTCL) are uncommon, but aggressive forms of non-Hodgkin lymphoma that develop from mature T cells, a type of white blood cell. The most prevalent subtypes include PTCL-NOS (not otherwise specified), AITL (angioimmunoblastic T-cell lymphoma), and ALCL (anaplastic large cell lymphoma). Patients with PTCL are usually treated with a combination of chemotherapy agents, mostly commonly CHOP (cyclophosphamide, adriamycin, vincristine and prednisone). With the exception of a rare variant called ALK-positive ALCL, only about a third of all patients could enjoy long-term disease-free survival, with most patients either having diseases resistant to treatment or recurrent after chemotherapy. As PTCL evolves, it becomes even more molecularly complex due to factors in the tumor microenvironment that make it hard to treat. Ongoing research has been performed in order to try and improve treatment options and increase overall survival for patients with this challenging disease.

To ultimately cripple tumors in patients with PTCL and eradicate the disease from the body, it’s necessary to target the molecular feature of PTCL that helps it grow. Leandro Cerchietti, M.D. Jia Ruan, M.D., Ph.D., and other collaborators from the Lymphoma Program at Weill Cornell Medicine and NewYork-Presbyterian are trying to do just that. New research conducted by the team has shown positive results for this hard-to-treat cancer.

Dr. Cerchietti and his research group have discovered that PTCL are sensitive to THZ1, a drug that targets transcription, the first step during gene expression when DNA is copied into RNA. THZ1 was developed by Dr. Nathanael S. Gray and collaborators from the Dana-Farber Cancer Institute. THZ1 works by stopping an enzyme called CDK7 (cyclin-dependent kinase 7) that controls the transcription of lymphoma genes. This interference changes the cells and primes the tumor to better respond to biologic agents, such as BCL2 inhibitors.

For this work, Dr. Cerchietti’s Lab established a collaboration with Drs. Nathanael S. Gray from Dana-Farber and Graciela Cremaschi from the Institute for Biomedical Research and the National Research Council of Argentina. After testing more than 120 FDA-approved compounds and new biologic agents from the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health and the Meyer Cancer Center Pre-Clinical Oncology Pharmacy, the investigators found that PTCL are susceptible to inhibitors of the proteasome, epigenetic drugs and compounds that target transcription, like THZ1.

tcell-lymphoma-graphic_cerchietti_thz1According to Cerchietti, they decided to focus on THZ1 since it demonstrated pre-clinical activity against PTCLs harboring the hard-to-target mutation STAT3. STAT can drive T-cell lymphomas and other tumors when activated by extracellular signaling that involves the phosphorylation of intermediate proteins like JAK. Although inhibitors of JAK proteins have been developed, they are thought to be inactive in tumors harboring the STAT3 mutation that does not require the activity of JAK. STAT proteins drive tumors by inducing the transcription of oncogenes like MYC and BCL2. Since this process requires CDK7, THZ1 can decrease the activity of STAT and the production of BCL2 and other proteins.

“Growing scientific evidence supports CDK7 inhibition as a treatment approach for cancers that are dependent on a high and constant level of transcription,” said Dr. Cerchietti. “Targeting CDK7 with THZ1 offers a way to circumvent the aggressive pathway responsible for tumor growth in many cancers, but particularly T-cell lymphomas which respond more positively to BCL2 inhibitors.”

BCL2 inhibitors are a class of drugs that are being tested to treat a variety of blood cancers. Venetoclax is an FDA-approved BCL2 inhibitor that is used to treat chronic lymphocytic leukemia (CLL) with a specific mutation.

“We are excited about these research results and the potential to bring a new treatment to patients with this aggressive lymphoma who otherwise have very few options if their cancer does not respond to chemotherapy,” said Dr. Ruan who leads the T-cell lymphoma clinical program at Weill Cornell Medicine and NewYork-Presbyterian.

“We aim to create transformative medicines that control the expression of disease-driving genes and believe this treatment can provide a profound and durable benefit for patients with a range of aggressive and difficult-to-treat solid tumors and blood cancers,” said Nancy Simonian, M.D., CEO of Syros, the biopharmaceutical company that is developing a next-generation version of the THZ1 compound for clinical trials. “Building on this research, we’ve used THZ1 as the starting point to create a selective CDK7 inhibitor that has better drug-like properties for use in humans.”

According to Syros, a phase I clinical trial built on this research is slated to open later this year to test the dosing and safety in people with solid tumors. The company plans to expand into hematological malignancies once the appropriate dose has been established in the initial phase I trial.

The bulk of this work was supported by the Leukemia and Lymphoma Society through a Translational Research Program awarded to Dr. Cerchietti.

Additional Weill Cornell Medicine contributors to this research include: Florencia Cayrol, Pannee Praditsuktavorn, Tharu Fernando, Rossella Marullo, Nieves Calvo-Vidal, Jude Phillip, Benet Pera, ShaoNing Yang, Kaipol Takpradit, Lidia Roman, Marcello Gaudiano, Ramona Crescenzo and Giorgio Inghirami.

Lymphoma Physicians Discuss Lenalidomide Plus Rituximab as Initial Mantle Cell Lymphoma Treatment

Recently Dr. John Leonard was interviewed by the Lymphoma Research Foundation and answered questions about the current state of treatment for patients with mantle cell lymphoma (MCL). Specifically, they discussed how results from the 2015, New England Journal of Medicine published study, “Lenalidomide plus Rituximab as Initial Treatment for Mantle Cell Lymphoma” has improved the treatment options for MCL patients. This multi-center phase 2 study showed that a combination therapy, lacking many of the typical debilitating effects of traditional cancer treatment could effectively manage MCL by inducing remissions in the vast majority of patients.

Dr. Leonard, the study’s senior author, described the potential impact of this research and how it could improve our understanding of MCL and treatment as follows,

“This research provides an additional option for patients with MCL and represents the first study of a non-chemotherapy approach that is generally of lower intensity than usual initial treatment. The fact that the majority of patients had durable disease control, with good quality of life, suggests that this approach may have value for some patients. Ongoing research will better assess the longer term outcomes with this approach, and how it either compares with or can be combined with other treatments. This study demonstrates the value of potentially using newer agents as part of initial treatment in MCL, rather than holding off until the disease recurs later.”

In April 2016 the study was nominated by the Clinical Research Forum as one of their Top 10 Clinical Research Achievement Awards of 2016. The 10 winning papers were chosen based on their degree of innovation from a pool of more than 40 nominations from 30 research and academic health centers nationwide.

In the video below you can watch the study’s lead author Dr. Jia Ruan describe the importance of her team’s findings.

New Clinical Trial: A Phase 1/2 Study to Assess the Safety & Tolerability of Durvalumab as Monotherapy & in Combination Therapy in Subjects with Lymphoma or CLL

The Weill Cornell Medicine Lymphoma Program has recently opened a new clinical trial for men and women with relapsed/refractory lymphoma or relapsed/refractory chronic lymphocytic leukemia (CLL). The study sponsor is Celgene International, and the principal investigator at Weill Cornell is Jia Ruan, M.D., Ph.D. For more information about the study, please call Catherine Babaran, RN at 212-746-2651 or e-mail Catherine at cmb9017@med.cornell.edu.

Key Eligibility

  • Men and women age 18 years and older.
  • Patients with relapsed/refractory lymphoma or relapsed/refractory CLL previously treated with at least one systemic therapy.
  • Detailed eligibility reviewed when you contact the study team.

Study Summary

This clinical trial is for men and women with relapsed/refractory lymphoma or relapsed/refractory chronic lymphocytic leukemia (CLL) previously treated with at least one systemic therapy.

The purpose of this study is to test the safety and effectiveness, as well as to define the appropriate dose and schedule of an investigational drug and investigational combinations of drugs. Durvalumab is an antibody (a protein that works with your immune system) that attaches to a molecule known as “programmed-cell-death ligand 1” (PD-L1). Signals from PD-L1 help cancers avoid detection by the immune system. Durvalumab blocks these signals, interfering with the cancer’s ability to escape the immune system.

The study will consist of 3 parts: dose findings, dose confirmation, and dose expansion. Four treatment arms will be investigated:

  • Arm A (durvalumab plus lenalidomide and ritxuimab)
  • Arm B (durvalumab plus ibrutinib)
  • Arm C (durvalumab plus bendamustine and rituximab)
  • Arm D (durvalumab monotherapy)

Study subjects will receive treatment for approximately one year and be in follow-up for anywhere from two to five years after treatment.

During each 28-day treatment cycle, subjects will receive durvalumab infusion on Day 1 of Cycles 1 through 13 at a fixed dose of 1500 mg every 4 weeks in combination with:

  • Arm A: Lenalidomide orally once daily on Days 1 to 21 of each cycle for 12 months or until disease progression plus rituximab infusion on Days 2, 8, 15 and 22 of Cycle 1 and on Day 1 of Cycles 2 through 5.
  • Arm B: Ibrutinib continuous, once daily until disease progression.
  • Arm C: Bendamustine infusion on Days 1 and 2 of Cycles 1 through 6 plus rituximab infusion on Day 2 of Cycles 1 through 6.
  • Arm D: Durvalumab monotherapy arm.