• Increase
  • Decrease
  • Normal

Current Size: 100%

Ed Forum 2016

Future Directions

This section of the website reviews some of the recent cutting edge research into the biology and genetics of WM and where this research may lead us. Fair warning – some of the links included here lead to journal articles which are technical in nature and may be difficult to understand by those without a scientific background. Also, keep in mind that some of this work is still preliminary and that not all of it will come to fruition – that is the nature of research, after all. However, we hope that much of it will result in a better understanding of what makes WM “tick” and lead to targeted and more personalized treatments. Indeed, we are already beginning to see such results.

New Strategic Research Roadmap for WM

In 2008 the IWMF, the Leukemia & Lymphoma Society (LLS), and the Lymphoma Research Foundation convened a special meeting to identify research priorities in the search for a cure for WM. From that meeting, three major research priorities were developed: the need for a WM tissue bank, the need for better and more representative WM cell lines, and the need for a mouse model of WM. Subsequent projects, funded by the IWMF alone and in concert with the LLS, led to substantial success in these areas.

Because of recent new and exciting developments in the areas of cancer biology and personalized medicine, the IWMF decided in 2014 that the time was right to update its research strategy and enlist the cooperation of many of the major players in the WM research community. To this end, the IWMF partnered with LLS to sponsor a Strategic Research Roadmap Summit in New York City on May 16-17, 2015.

Dr. Lee Greenberger, Chief Scientific Officer of LLS, moderated the Summit, which was attended by the following notable WM researchers: Dr. Ranjana Advani of Stanford University, Dr. Stephen Ansell of Mayo Clinic in Rochester, Dr. Asher Chanan-Khan of Mayo Clinic in Jacksonville, Dr. Morton Coleman of NY Presbyterian Weill Cornell, Dr. Shirley D’Sa of University College in London, Dr. Richard Furman of NY Presbyterian Weill Cornell, Dr. Irene Ghobrial of Dana-Farber Cancer Institute, Dr. Zachary Hunter of Dana-Farber Cancer Institute, Dr. Larry Kwak of City of Hope, Dr. Robert Kyle of Mayo Clinic in Rochester, Dr. Ari Melnick of NY Presbyterian Weill Cornell, Dr. M. Lia Palomba of Memorial Sloan Kettering Cancer Center, Dr. Roger Owen of St. James’s Institute of Oncology in Leeds, and Dr. Steven Treon of Dana-Farber Cancer Institute. Dr. Ansell and Dr. Treon were the scientific co-leaders of the conference.

The IWMF was represented by its President, Carl Harrington, and its Vice President for Research, Dr. Guy Sherwood. In addition to Dr. Greenberger, other attendees from LLS included Dr. Erik Nelson, Director of Research Programs, and Dr. Yixian Zhang, Executive Research Director.

The Summit agenda was divided into four major topic areas, with two-person teams leading the discussion of each topic:

  • Signaling – What pathways do WM cells use for communication?
  • Immunology/immunotherapy – How can we better use our own immune system to fight WM?
  • Tumor microenvironment – How does the bone marrow environment affect WM cells?
  • Omics – What else can we learn about genomics, epigenomics, and WM mutations?

Part of the Summit was also set aside for presentations by pharmaceutical companies actively working on treatments for WM, including Vivolux, Pharmacyclics, Nimbus, Argen-X, and Idera.

An explanation of the four major topic areas on the Summit agenda is offered by Dr. Stephen Ansell of the Mayo Clinic, scientific co-leader of the Roadmap Summit, in a short video entitled "An Exciting Time in Waldenstrom's!"

As a result of the Summit, the IWMF-LLS Strategic Research Roadmap Initiative was developed. The Initiative is expected to fund and implement 4-5 new research projects for 2 years, with the possibility of an extension for 1-2 additional years depending on the progress achieved, at a cost of roughly $200,000 per year per project for a total annual cost of roughly $1,000,000. This dynamic plan would initially seek to fund 2-4 research projects in year one (with the possibility of additional research projects in subsequent years depending on available funding). To achieve this plan, the IWMF identified the following steps:

  • The development of a Request for Proposals (RFP), issued globally on November 11, 2015. The Request for Proposals can be viewed here.
  • The deadline for receipt of year one proposals was February 19, 2016.
  • Notification of awards was made in June 2016.
  • Anticipated funding start date will be July-October 2016.

The first awards resulting from the Request for Proposals were made to the following recipients:

  • Dr. Madhav Dhodapkar from Yale University: "Origins and immunotherapy of macroglobulinemia"
  • Drs. Christian Buske, Jan Münch, and Daniel Sauter from Ulm University in Ulm, Germany:  "Characterization of endogenous CXCR4 inhibitory peptides to target WM"
  • Dr. Marcel Spaargaren from Academic Medical Center in Amsterdam, the Netherlands: "Towards a rational targeted therapy for WM by kinome-centered loss-of-adhesion and synthetic lethality screens"

A second Strategic Research Roadmap Summit was held in May 2016. At that time, it was decided to hold yearly Summits in order to keep the participants updated on the progress made in each area of the Roadmap and to make revisions to the Roadmap as needed. It is also the intent of the IWMF and LLS to continue to issue a yearly Request for Proposals under the Roadmap Initiative.
 

MYD88 L265P Mutation

Research into the genetics of WM made a major leap forward in 2011 with the discovery – by Dr. Steven Treon and his group at Dana-Farber Cancer Institute – of a single mutation in a gene called MYD88, with a prevalence in 90% or more of WM patients. This was the first time that the entire genome, or complete set of DNA, of patients with WM was sequenced. The goal was to determine which genes were present in the cancer cells of these patients that were not seen in their normal cells. The IWMF was a sponsor of this research. The same study also reported that the MYD88 mutation, designated MYD88 L265P, was not nearly as prevalent in most other types of lymphoma or in multiple myeloma. This groundbreaking study is available here. Subsequent follow-up studies by WM investigators around the world have validated these findings.

Although we do not yet know the role that the MYD88 mutation plays in the development and progression of WM, Dr. Treon’s group and others have continued to study the mutation’s effects on downstream cellular pathways. Researchers now have a fairly good idea of the complex pathways affected by this mutation and how they might in turn promote the growth and proliferation of WM cells. A summary of some of this follow-up work can be found here.

As a result of this work and its subsequent confirmation by other researchers, the US National Comprehensive Cancer Network (NCCN) recently updated its guidelines for WM to include AS-PCR testing for the presence of MYD88 L265P in the bone marrow cells of suspected patients and has characterized the test as essential for the diagnosis of WM.

The IWMF is also funding work by Dr. Treon and his team to study several potential therapies that target cellular pathways downstream from MYD88, and preliminary results are encouraging. Stay tuned…...

CXCR4 Mutations

Several other genetic mutations were discovered to be fairly common in WM patients, although not to the extent of the MYD88 L265P mutation. One such group of mutations occurs in the gene CXCR4 at a prevalence rate of about 30%. Studies suggest that such mutations cause significant tumor proliferation and spread to extramedullary organs (outside the bone marrow), thereby leading to disease progression and a less favorable prognosis. The CXCR4 mutations are discussed in much more detail here. Additional research is being funded by the IWMF to confirm these findings, to determine the mechanisms by which these mutations cause disease progression, and to test an inhibitor of CXCR4 to see if it has potential to be used as a treatment for WM patients who harbor CXCR4 mutations.

Novel Treatments Based on Targeted Cellular Pathways

Our rapidly expanding knowledge about the cellular pathways involved in the development and progression of blood cancers, including WM, is now being applied to translational research, which takes this basic research and converts it into the synthesis of treatments that are targeted to these pathways.

Two of the newer treatments already in clinical use for WM include ibrutinib (Imbruvica), which targets Bruton’s tyrosine kinase (BTK), and everolimus (Afinitor), which inhibits mechanistic target of rapamycin (mTOR). Both targeted molecules are downstream from MYD88. In a groundbreaking moment in the history of WM, Imbruvica was specifically approved for its treatment by the US Food and Drug Administration on January 29, 2015, in an announcement presented here. It has since been approved by the European Medicines Agency for use in the European Union and by Health Canada. Other treatments that target various pathways, including panobinostat, perifosine, idelalisib (Zydelig), ABT-199, and IMO-8400, are in clinical trials for WM and other blood cancers….information about these clinical trials can be found by searching www.clinicaltrials.gov. Others are in pre-clinical development.

These new targeted pathway treatments are different from traditional therapies in several ways, and these differences have important implications for patients. They are more specific for tumor cells than chemotherapy, which often damages normal cells. Almost all of them are oral medications administered daily or several times a week, which means that they can be taken at home. This makes them more convenient, but it also means that patients must be compliant about when and how to take their medication. These treatments do not damage stem cells in the bone marrow, although they all have side effects that may lead patients to discontinue their use. They can result in dramatic improvements in disease status, but they appear to slow or arrest tumor cell growth rather than completely eliminate the cancer.  This means that, once patients begin these treatments, they may need to continue until the treatments no longer work or until side effects become intolerable. This represents a significant change from the older therapies which are typically administered cyclically for a period of time and then discontinued after a patient achieves a response. Because cancer cells are very adept at developing resistance mechanisms, it is highly likely that combinations of targeted pathway therapies will be necessary, or that targeted pathway therapies will be combined with monoclonal antibodies, such as Rituxan.

The novel oral agents are very expensive, and not all insurers pay for them. Federal and state regulations are being changed so that Medicare, Medicaid, and private insurers may eventually be required to cover their cost to the same extent that they cover intravenous and injectable drugs (so-called “oral parity” laws), but for now this remains an ongoing issue for many cancer patients.

Adoptive T-Cell Therapy

Our own immune systems have the capacity to recognize and eliminate cancer. Individuals have billions of immune cells called cytotoxic T-cells, each of which recognizes a different foreign target and can destroy it. This specificity is conveyed by the “T-cell receptor” found on the surface of each T-cell. For instance, one T-cell receptor may recognize the flu virus while another may recognize the polio virus. A promising new type of cancer immunotherapy utilizes this property and engineers T-cells to recognize a patient’s own tumor cells. Large quantities of the engineered T-cells are reinfused into the patient so that they can destroy the cancer. This has been successfully and rather dramatically demonstrated in cases of leukemia, lymphoma, and melanoma, with reporting in mainstream publications.

Dr. Brad Nelson’s group from the Deeley Research Centre in Canada recently received joint funding from the IWMF and the IWMF affiliate WMF Canada for a study on the use of adoptive T-cell therapy in WM. These researchers have already identified cytotoxic T-cells that recognize the MYD88 L265P mutation, and they propose to use these T-cells as a starting point to clone a T-cell receptor that specifically recognizes the mutation. They will then generate large numbers of T-cells expressing this receptor and test the safety and effectiveness of these T-cells in preclinical mouse models. If successful by the end of the grant period, this group anticipates being in a position to conduct a Phase I clinical trial of these specialized T-cells in WM patients.

Section: 
Google Adwords: 

Did you know?

Did you know the goal of the IWMF Imagine a Cure campaign is to raise $25,000,000 to fight WM?