Reasons For Drug Failure

Bruce
Chabner
,
MD
Massachusetts General Hosp Cancer Center

Forum Description

Sessions:

  1. Introduction
  2. Transport Genes and Drug Resistance
  3. Multidrug Resistance and Carcinogenesis
  4. Clinical Studies of MDR
  5. Discussion of Approaches to Clinical Trials

In November 1987, the third annual Forum will deal with reasons for chemotherapy failure, a very important matter in attempts to improve the treatment for patients with cancer. Why do drugs work in one patient and not in another? Why in one patient will the tumor initially respond, and virtually disappear, and then recur in a matter of months or years with cancer cells that are resistant to those very same drugs? Are there ways to avoid drug resistance? When drug resistance occurs, are there maneuvers to overcome this resistance?

We know there are certain areas of the body, such as the brain, that are chemotherapy sanctuaries. This means that the drugs do not penetrate into these areas. Does this also play a role in drug failure? If inroads can be made in answering these questions, then chemotherapy treatment of patients with cancer will improve and the overall cure rate will also improve. The Forum on Reasons for Drug Failure will be chaired by Dr. Bruce Chabner, Director of the Division of Cancer Treatment at the National Cancer Institute, and one of the outstanding cancer pharmacologists in the world.

Forum Summary

Scientists from the United States, Canada and Japan met in November 1987 at Moss Creek Plantation in Hilton Head, South Carolina, to discuss multidrug resistance in cancer chemotherapy in the third Annual Think Tank of the William Guy Forbeck Foundation. The participants discussed the biochemistry and genetics of a special form of resistance to cancer chemotherapeutic drugs now known as multidrug resistance (MDR). MDR was first discovered by Dr. Victor Ling at the University of Toronto, who was the first to appreciate that cancer cells could become resistant to traditional chemotherapeutic drugs by developing a unique protein on the cell membrane. This protein functions to rid the cell of potentially toxic or dangerous compounds, and extrudes cancer drugs, among other compounds. Since Ling’s discovery, approximately 10 years ago, evidence has accumulated implicating this protein, P170, is resistant to a variety of cancer drugs, including some of the most effective agents for treating leukemia, lymphoma and childhood tumors.

The meeting was as called to bring together prominent researchers in this field to consider ways in which these results might be applied to improving cancer treatment in patients. The initial sessions of the meeting discussed the P170 glycoprotein and the genetic factors that control its expression in tumor cells. Investigators from Toronto, the National Cancer Institute in Bethesda, Maryland, and Cancer Chemotherapy Center in Tokyo presented their latest studies describing the gene that codes for this protein and initial work on its presence in a variety of human tumors. The protein is found in leukemia cells after treatment, in lymphomas after treatment, and in certain solid tumors, such as colon cancer, kidney tumors and adrenal gland tumors, both before and after treatment. More recent work subsequent to this meeting has now defined an important role for the MDR protein in additional diseases, including multiple myeloma. As a result of the meeting, clinical studies of P170 expression were initiated in the Pediatric Cooperative Groups and in Acute Leukemia Treatment groups.

The meeting considered analogous transport proteins in lower organisms, including a series of bacterial membrane-associated transporters. Dr. Giovanna Ames from the University of California presented evidence that P170 protein has homology in its ATP binding regions with histidine and multose permease systems in bacteria, and proposed that it might represent a fusion of two transmembrane subunits of the bacterials permeases; possibly the bacterial protein has since been adapted for other functions in mammalian cells.

Work by Susan Horwitz at Albert Einstein College of Medicine evoked considerable interest. She showed that a radioactive calcium channel-blocking compound, azidopine, could be used to label the protein at the drug surface. This test is now widely used in studies of drug binding to P170 and, indeed, to identify the presence of the protein in tissues.

Alternatives to P170 as the use for multidrug resistance were then discussed by investigators from the National Cancer Institute. Charles Myers, Chief of the laboratory of Clinical Pharmacology, provided evidence that of other proteins, including glutathione – S- transferase, are altered in drug- resistant cells, and raised the possibility that these enzymes could contribute to multidrug resistance. Subsequent work has clearly shown that this is the case and has implicated a set of DNA-cleaving proteins, called topoisomerases, as alternative causes of multidrug resistance.

In summary, the conference provided a special opportunity to consider developments in this rapidly evolving field. Collaborations between various investigators were established, particularly with respect to sharing reagents such as DNA probes and antibodies, and collaborative experiments were begun in the area of genetics and clinical laboratory collaborations.

The fruits of this meeting were much in evidence at a recent conference on the subject (April 10- 11, 1989, in Bethesda), where the Forbeck participants presented the results of a number of collaborative studies. Among these, the work of Ronnison from the University of Illinois, Pastan, Gottesman and Fojo from the NCI, Horwitz from Einstein, Tsuruo from Tokyo, and Ling from the University of Toronto provided further evidence for a role of the P170 protein in clinical drug resistance and the possibility of reversing drug resistance with antibodies and calcium channel-blocking drugs.

Venue & Travel Information

Hilton Head Island

Travel Forms

TRAVEL FORMS DUE:
October 5, 1987
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, 1987
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

Giovanna Ferro-Luzzi
Ames
,
PhD
University of California Berkeley
Bruce
Ames
,
PhD
University of California Berkeley
Tito
Fojo
,
MD
National Cancer Institute
Michael
Gottesman
,
MD
National Cancer Institute
John S.
Holcenberg
,
MD
Children's Hospital of Los Angeles
Susan B.
Horwitz
,
PhD
Albert Einstein College of Medicine
Charles
Myers
,
MD
National Cancer Institute
Ira
Pastan
,
MD
National Cancer Institute
Barry
Rosen
,
PhD
Wayne State University School of Medicine
Howard
Shuman
,
PhD
Columbia University
Takashi
Tsuruo
,
MD
Japanese Foundation for Cancer Research

Forum Scholars

No Scholars attended this meeting