Lymphoma Program Establishes Partnership to Advance Development of Targeted Lymphoma Therapies

The Lymphoma Program has recently established a cross-campus experimental therapeutics collaboration between Weill Cornell Medical College and Cornell University. Known as the Progressive Assessment of Therapeutics, or P.A.Th. this partnership will harness the already existing infrastructure at the two university sites for the purpose of advancing a more rapid bench to bedside discovery process for the clinical introduction of targeted therapies.

Dr. Kristy Richards
Dr. Kristy Richards

The P.A.Th. program will be overseen by co-directors Dr. Kristy Richards and Dr. Leandro Cerchietti. Dr. Richards is an expert in comparative oncology and oncogenomics, which emphasizes the genetic/genomic approaches to understanding the biology and treatment of hematologic malignancies. Her research involves genetic mapping and genetic association approaches to understanding drug resistance in a variety of agents used to treat hematologic malignancies. Dr. Cerchietti is an expert in experimental therapeutics in lymphomas. His research involves developing of pharmacokinetic and pharmacodynamics biomarkers to personalize treatment regimens in pre-clinical and clinical settings.

Dr. Leandro Cerchietti
Dr. Leandro Cerchietti

In practice the collaborative program will improve the speed and accuracy of the clinical trial process, while streamlining the organization required to bring new treatments through the laboratory to the patient’s bedside. It has already seen tangible results in a recently published paper. This approach will have different manifestations. For patients with DLBCL, cell lines are the workhorse in the early development of treatments. However, the numbers and diversity of DLBCL cell lines is small, while more indolent lymphoma cell lines are difficult to maintain. Through the P.A.Th. program in collaboration with Dr. Ankur Singh of the Sibley School of Mechanical and Aerospace Engineering, researchers are developing 3-D tissue culture (organoids) on lattices that more closely simulate the micro-environment of a lymph node. This would allow for lymphoma cells taken from patients to be more successfully cultured and easily researched. The ease of developing and curating new and longer lasting cell cultures could lead to faster breakthroughs in the development of treatments.

Another focus of the P.A.Th. program is the use of better mouse models and the inclusion of pet dogs as a model for human lymphoma. Pet dogs can enroll in clinical trials, much the same way human patients can, yet this resource has mostly been overlooked.  Given Cornell University’s top-ranked veterinary school, and the high incidence of lymphoma in pet dogs, this is a resource that the P.A.Th. program is using to increase their clinical trial capacity in lymphoma research. This will save the lives of both 2 legged and 4 legged patients.

Taken together these improvements and others should make for a comparatively quicker and more accurate therapeutic development strategy. Considering, its multidisciplinary approach and high quality capabilities this collaboration is poised to be a leader in the development of new therapeutics for lymphoma. As Dr. Richards, noted, “Think of this P.A.Th. program as a bridge that connects the incredible lymphoma basic and translational research that is already happening throughout the Cornell campuses, with Cornell’s excellent patient care. The results will provide a very compelling therapeutic development strategy that should provide hope to patients with lymphoma and other types of cancer.”

New Developments in Lymphoma – Winter 2015 Newsletter

The Lymphoma Program has published the winter 2015 edition of the New Developments in Lymphoma Newsletter.

Please look to this space for further announcements of future newsletter issues, or sign up for advance notice of the newsletter here.

Transcription Regulation Targeting Presents Potential New Paradigm in Treating Patients with Peripheral T-cell Lymphoma

lecBy Leandro Cerchietti, MD

Peripheral T-cell lymphomas (PTCL) are a clinically aggressive disease with poor responses to current modes of therapy and a dismal survival rate. In an abstract presented before the 56th annual American Society of Hematology conference we sought to identify an active new drug for PTCL patients.

We began by performing a cell-based progressive screen from a library of 105 anti-neoplastic drugs in clinical use. Initially within the clinical-range limit we identified 3 active drugs groups HDAC inhibitors (HDI, romidepsin), proteasome inhibitors (bortezomib, carfilozimib), and transcription inhibitors (dactinomycin). Secondary screenings were conducted for the active drug groups with six drug concentrations, in an extended panel of 9 TCL cell lines. To expand the scope of our drug groups we added vorinostat, panobinostat and valproic acid for HDI and SNS032 (CDK9>2>>7 inhibitor) and THZ1 (CDK7>12 inhibitor) for transcription inhibitors.

We found that the most active drugs were bortezomib, carfilzomib, romidepsin, dactinomycin, and THZ1, focusing on the transcriptional inhibitors, using THZ1 to investigate the functional relevance of CDK7/12 targeting in PTCL. THZ1 was found to decrease mRNA and protein levels of MCL1, JAK1, and MYC as early as 3 hours into treatment. The levels of anti-apoptotic proteins BCL2, BCL-XL, JUND, and NFkB also decreased, while proteins like the pro-apoptotic BAX increased.

In conclusion we found a mechanism by which CDK7/12 inhibition with the compound THZ1 simultaneously inhibits prominent PTCL survival pathways, causing apoptosis and re-sensitization to BCL2-family inhibitors. These findings led us to identify a mechanism by which CDK7/12 inhibition and presents a potential new paradigm in treating patients with PTCL.