The Biology And Treatment Of Primary Brain Tumors

Tracy
Batchelor
,
MD, MPH
Harvard Medical School
Luis F.
Parada
,
PhD
UT Southwestern Medical Center

Forum Description

Sessions:

  1. From Models of Brain Tumors to Clinical Trials
  2. Tumor Origin, Medulloblastoma and Mechanisms
  3. The Problem of Angiogenesis
  4. Platelet Derived Growth Factor (PDGF), Alternative Tumor Sources and Implications

Primary tumors of the central nervous system are the leading cause of cancer death in children, and a tumor of growing incidence in adults, in whom it is equally difficult to treat. Only recently have researchers begun to understand the basic genetic derangements that play a central role in the growth of these tumors. In children, brain tumors are found in a variety of unusual types, some with unique and characteristic appearance on pathologic examination and in their clinical behavior. In adults, primary brain tumors usually arise in astrocytes, supporting cells of the nervous system, and, in their most common, and poorly differentiated form, these tumors, called gliomas, are exceedingly difficult to treat with any of the common approaches (surgery, chemotherapy, or radiation therapy). Major efforts are now underway to elucidate the genetic changes in these tumors, the pathways and receptors activated by these changes, and the changes found in the tumor micro-environment. Animal models for some of these kinds of brain tumors have now been developed, and are providing information on tumor behavior and response to experimental treatment. New clinical trials are finding that these tumors are highly dependent on new blood vessels, and respond to treatments that destroy these vessels.

Abnormal receptors and activated growth pathways are found on the cell surface or inside these tumors and these may be the subject of new treatments as well. New information indicates that multiple aberrancies may exist in the signaling PORTFOLIO of these tumors, thus requiring multiple sites of attack. In this rapidly evolving state of knowledge, the meeting, to be led by Dr. Tracy Batchelor of the Massachusetts General Hospital's Cancer Center, and Dr. Luis Parada of University of Texas Southwestern Medical Center, should provide an exciting opportunity for bringing together leaders in the genetics, biology, and treatment of this important group of tumors.

Forum Summary

The focus of the 2009 Forbeck Foundation meeting in Hilton Head was primary brain tumors. These are a leading cause of cancer death in children. Although their occurrence in adults is relatively rare, the tumors can be very aggressive with poor survival rates. In adults, primary brain tumors usually arise in cells called astrocytes, which are thought of as the supporting cells of the nervous system. These cells, in their poorly differentiated form, can produce a tumor type called gliomas, which are exceedingly difficult to treat with any of the common approaches (surgery, chemotherapy, or radiation therapy).

Major efforts are now underway to elucidate the genetic changes that can occur in specific types of brain tumors. This can lead to the identification of either abnormal receptors and/or activated growth pathways that may aid the development of new, much needed, therapies. Animal models for some of these tumors have now been developed, and can also provide information on their behavior and response to experimental treatments.

New clinical trials are finding that gliomas are highly dependent on new blood vessel development. Our understanding of how the tumor cell communicates with host blood vessels to increase their rate of division and thus their number offers a new approach to destroying the cancer cells if therapies can be developed to specifically destroy these vessels. In this field there is a desperate need to define new approaches to treatment. Dr. Tracy Batchelor of Massachusetts General Hospital Cancer Center, and Dr. Luis Parada of the University of Texas Southwestern Medical Center, brought together a group of clinicians and basic scientists to review new information on the development and treatment of brain tumors. Dr. Peter Dirks reviewed his work on the identification of cell populations with stem cell like properties in mouse models of medulloblastoma (a pediatric tumor) and glioma. He reviewed the importance of culture conditions in the enumeration of these cells and the evidence that these cells maintain their tumorigenic properties in vivo. The identification and characterization of these cell populations could lead to the development of drug screening platforms to identify agents that target cancer stem cells that are present in these tumor types. Dr. Luis Parada reviewed data provided by Lynda Chin from The Cancer Genome Atlas (TCGA) study. Glioblastoma was the first tumor selected for genomic screening in this large-scale national project. Investigators probed glioblastoma for the expression of 600 well-characterized, cancer-associated genes. There were six major genetic techniques may tell us more about the biology of malignant brain tumors and may offer a non-invasive means of monitoring physiological changes in these tumors during therapy. Dr. Greg Sorensen reviewed the use of these MRI techniques in a study of 31 glioblastoma patients in which a number of biological effects of anti-VEGF therapy were detectable. MRI techniques are being developed to predict patients who will or will not respond to anti-angiogenic therapy. Dr. John Ebos reviewed the potential adverse effects of anti-angiogenic agents including provocative data generated in mouse models of cancer that anti- angiogenic therapies, in the form of receptor tyrosine kinase inhibitors, may increase the metastatic potential of certain tumor types. These observations raise potentially important questions regarding the timing of anti-angiogenic therapy and the possible benefit of drug combinations to reduce the possibility of this effect.

The importance of the brain tumor microenvironment was highlighted and reviewed by Dr. Gabrielle Bergers. The beneficial effect of bevacizumab on brain tumors is transient and the tumor eventually becomes more invasive through a number of potential pathways. She reviewed preclinical glioma models that implicate a number of cytokines, c-MET, SDF1, in this switch to a more infiltrative tumor growth pattern. Possible molecular targets to prevent or reverse this invasive tumor growth were reviewed.

A session was chaired by Dr. Chuck Styles and emphasized the use of mouse models to study glioma. Dr. Kwon presented his very preliminary studies in which he is using material derived from NF1; p53;Pten based tumor models to identify genes that are transcriptionally modified in a significant way compared to the expression in neural progenitors which are the source for these tumors. He has used these data to compare with the TGCA data and find commonalities. As a first example of his proposed method, Dr. Kwon has identified a gene that is highly expressed both in human and mouse tumors and that is implicated in controlling reactive oxygen species, a potentially damaging agent in tumor development. He discussed the methods of validation of this gene and moreover the approaches he plans to take to identify additional genes in a high throughput manner. This was a good platform for discussion of the many technical obstacles the field is faced with. Dr. Holland discussed his PDGF inducible glioma mouse models in the context of Ink4a/Arf null background. Injection of a retrovirus with either a nestin or GFAP promoter can induce tumor development and he proposes this as a powerful model to study tumor development of PDGFR sub-classes. Dr. Holland presented some mathematical models that would support the stochastic capacity of tumor formation as a function of the rate of mutation and proliferation in the pool of potentially tumor forming cells. In this scenario, in principle, any cell could undergo the appropriate number of mutations to give rise to glioma. In another set of experiments in which his group uses side population FACS sorting to enrich for tumor cells, Dr. Holland demonstrated that agents such as temozolimide enrich this population resulting in more aggressive tumorigenic cells. Dr. Becher studies diffuse infiltrating pontine gliomas, a very rare but terrible form of glioma in children. These tumors arise in the Pons and are very aggressive. In a novel set of experiments Dr. Becher provided compelling evidence that he can successfully model this rare tumor in mice. This is a huge advance since due to their rarity, material to study these tumors is very difficult to obtain. Dr. Becher plans to use this model to identify therapeutic targets that may enhance the treatment of this disease. In the final session, Dr. Parada expanded on the discussion of physiologically relevant mouse models and their potential to provide more informative and a quantitative evaluation of therapeutic modalities. The cancer stem cell hypothesis was further discussed in a continuation of discussion broached by Drs, Holland and Wechsler-Reya, among others. The value of continued development of models not only for validation and biological studies but also as improved pre-clinical models of glioma was discussed.

In summary, the meeting embodied many of the current and timely topics that surround continued efforts by both clinicians and basic scientists to tackle this devastating disease that is not curable. It can be said that there was a dynamic, candid, and open-minded discussion that served to both educate both sides of this front and to identify possibilities for collaboration.

Quotes from Participants “It was 3 most stimulating days, with a lot of interesting exchanges allowing for novel ideas and new collaborations.” -- Roger Stupp, MD, University of Lausanne, Lausanne, Switzerland

“… such a great platform for the brain storming sessions. I truly enjoyed those tremendously, learned a lot and got some new vision. The restrictions of five slides were perfect for the discussions.” -- Gabriele Bergers, University of California, San Francisco, CA

Venue & Travel Information

Hilton Head Island

Travel Forms

TRAVEL FORMS DUE:
October 5, 2009
submit travel form

Travel Policy

Please familiarize yourself with our policies and procedures for travel. We truly appreciate you taking the time to participate in this meeting. As you make your plans, please remember that we are a nonprofit organization dependent on donations and volunteers. We do NOT pay for upgrades, change fees, incurred costs resulting from a flight change, transportation to or from your local (home side) airport, meals or other incidentals.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.
  • Spouses are welcome to come with you at their own cost but are not allowed to attend the meeting. Please no children.

What the Foundation Pays

Accommodations and meals are provided by the foundation during the meeting. Airfare will be covered only if booked through our travel agent. The Foundation will also cover airport transportation on the meeting side at the designated shuttle times. You can select not to utilize Foundation arranged transportation at your own expense when completing the travel form. Once your travel form is received your accommodations and airport transfer will be confirmed. Please let us know of any food allergies or other information we should be aware of on the travel forms.

  • If you would like your airfare covered by the Foundation, you must book with our travel agent. Note we do not cover upgrades, changes, late bookings, etc.
  • Flights must be booked at least 30 days prior to the meeting to confirm your accommodations and airport transfer.
  • As a nonprofit we utilize volunteers and other methods to maximize our efforts (or our donor support) when making accommodations and arranging ground transportation. Ground transportation will be provided upon your arrival either by a foundation volunteer or arranged shuttle. You will be provided airport transportation information the week of the meeting. We do not reimburse for home side airport transfer or incidentals while traveling.

Abstracts

Abstracts are due 30 days prior to the start of the meeting to allow enough time to prepare the meeting book.

The abstracts should be only one or two paragraphs outlining the theme of your presentation and should reflect the objective and spirit of the meeting (see above). Abstracts will be circulated about one week before the meeting. The meeting organizer will start requesting them a month before the meeting.

abstracts DUE:
October 5, 2009
submit abstract

Meeting Structure

The meeting structure has been developed over years of experience.

  • Participants have approximately 45 minutes, depending on the number of participants, for their presentation and discussion. The presentation is meant as a conversation start and should last about twenty minutes briefly covering background information and areas that are new or need further input. This should be structured in such a way as to lead to a lively discussion. Participants are encouraged to interrupt to ask questions or start discussions.
  • A MAXIMUM of 5 slide equivalents per presentation is allowed (Power point slides should not contain more than one graph or gel per slide and no more than 5 bullet points to stress the points being made by the presenter.) We appreciate cooperation with the spirit of this guideline. Handouts are welcome but should be distributed before sessions.
  • Everyone is expected to actively participate in every session and discussions.
  • The time spent at the meeting is relatively short, so please be familiar with papers received prior to the meeting.
  • It is very important that you commit to all sessions of the 2 days of meetings.

Forbeck Scholars Participation

Scholars are selected for each Forbeck Forum. These are outstanding junior clinical or post-doctoral fellows selected based on the quality and relevance of science.

  • Scholars present for 30-45 minutes, depending on the number of participants
  • The same presentation rules apply for scholars
  • After the Forum you are selected to attend, you will attend three years of Scholar Retreats held in Lake Geneva, WI. If you attend a Fall Forum, you will attend the Spring Retreat. If you attend a Spring Forum you will attend a Fall Retreat.
  • Scholars are selected by the Foundation Scientific Advisory Board and peer reviewers selected from past Forbeck Scholars.

General Program

The outline below illustrates a typical program schedule. You will receive a complete schedule, including speaking times, the Thursday the meeting starts.

Arrival Day
1:00 PM Arrivals
6:00 PM Cocktails (opt'l)
7:00 PM Dinner
Meeting Day 1
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Meeting Day 2
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Departure Day
7:00 AM Breakfast
8:00 AM Departures

Frequently Asked Questions

Below are some of our most Frequently Asked Questions. If you have something new to ask, please feel free to contact us.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • Frequently airport transfer is provided by volunteers. Please be patient on receiving this information. Airport transfer will be sent out prior to arrival.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.

Forum Participants

Gabriele
Bergers
,
PhD
University of California San Francisco
Lynda
Chin
,
MD
Dana-Farber Cancer Institute
Peter
Dirks
,
MD
University of Toronto
Dan G.
Duda
,
DMD, PhD
Massachusetts General Hospital
John M. L.
Ebos
,
PhD
University of Torino
Eric
Holland
,
Memorial Sloan Kettering Cancer Center
Mikkel
Noerholm
,
Massachusetts General Hospital
Greg
Sorensen
,
Massachusetts General Hospital
Charles D.
Stiles
,
PhD
Dana-Farber Cancer Institute
Roger
Stupp
,
MD
University of Lausanne
Robert
Wechsler-Reya
,
PhD
Sanford-Burnham Medical Research Institute

Forum Scholars

Oliver Ayrault, PhD
Institute Curie
Oren Becher, MD
Duke University
Clark C. Chen, MD, PhD
University of California San Diego
Chang-Hyuk Kwon, PhD
Ohio State University Medical Center