Telomerase-Mediated Telomere Targeting in Cancer

Titia
De Lange
,
PhD
Rockefeller University
Jerry W.
Shay
,
PhD
UT Southwestern Medical Center

Forum Description

As humans age, the ends of linear chromosomes, telomeres, become progressively shorter. Short telomeres elicit a DNA damage response that leads cells to stop dividing and undergo senescence or apoptosis. This process inhibits the outgrowth of cancer cells that have undergone an abnormally high number of cell divisions. However, rare cancer cells can activate a cellular reverse transcriptase, telomerase, to reconstitute functional telomeres. Telomerase is absent in most normal tissues but is detected in the great majority of clinically detectable cancers. Thus, while telomerase is not oncogenic per se, it is almost universally required to permit the indefinite growth that occurs as part of cancer progression. Therefore, the inhibition of telomerase is an attractive target for cancer therapeutics. There have been several approaches to targeting telomerase in cancer in the past but none have advanced to late stage clinical trials. Thus, it is timely to review the progress and future directions for targeting telomerase in this Forbeck conference. Topics will include a discussion on why progress has been slow and how going forward this may change using new approaches. There will discussions on human genetic disorders affecting telomeres, alternatives to telomerase in a subset of tumors and the role of senescence as an initial brake preventing premalignant cells from progressing to advanced cancers.

Forum Summary

In Summary (very briefly) how would you explain what was covered in this forum. Simplest terms.
The past meeting, held in Denver from October 17-19, was the second Forbeck meeting on telomere biology. Since the last meeting, 17 years ago, great progress has been made in the field and several cancer-relevant aspects of telomere biology as it relates to cancer were discussed vigorously. Relevant to neuroblastoma, a recent meeting in the UK addressing new drug development strategies for this disease as well as a recent publication, reported that patients with high telomerase activity have overall poorer outcomes. We had a detailed discussion on how to target telomerase in cancer, exploring the pros and cons of telomerase inhibitors and so-called telomerase poisons, one of which has already been shown to be effective in neuroblastoma cell lines. We also discussed the potential deleterious consequences of telomerase inhibition based on new clinical knowledge of inherited telomere diseases which mimic telomerase insufficiency.

Several clinicians discussed the challenges of treating such patients as well as the implications of patient data for understanding the role of telomeres in cancer. An important aspect of our discussion focused on recent new findings that indicate that children born with overly long telomeres are predisposed to cancer. In addition, we discussed the mechanisms by which loss of telomeres drive changes in the cancer genomes and the potential of gleaning actionable information from the current NextGen cancer genome sequencing efforts. Finally, a considerable part of our discussion was focused on a second pathway for telomere maintenance, called ALT. The ALT pathway is highly significant to neuroblastoma since a substantial number of patients have cancers that employ this pathway. This pathway has been known for a long time but was poorly understood. Recent progress now has revealed the details of how ALT works and is beginning to suggest how ALT could be targeted in the cancer clinic.

Why was this meeting relevant now?
As humans age, the ends of linear chromosomes, telomeres, become progressively shorter. Short telomeres elicit a DNA damage response and can induce either senescence or apoptosis both of which can halt tumorigenesis. Telomerase, the enzyme that elongates telomeres, can counteract telomeres shortening and prevent senescence and apoptosis. This enzyme is absent from most normal tissue but is often activated in cancer. Recently it has become clear that telomerase activation is a highly selected aspect of tumorigenesis, often occurring through point mutations in the promoter of the gene encoding the limiting component of telomerase. While telomerase is not oncogenic per se, it is almost universally required to permit the indefinite growth that occurs as part of cancer progression. The recent data on mutational telomerase activation has confirmed the view that telomerase is a required aspect of cancer cell proliferation and further supports the view that inhibition of telomerase should be an effective cancer therapeutic. These and other new data on telomeres and the role of telomeres in cancer made the discussion in the context of the Forbeck forum highly appropriate and timely.

The meeting was viewed as highly successful by all participants and several new collaborations were initiated at the meeting. The Forbeck scholars were all excellent and participated throughout the meeting in a very productive manner.

What came out of this meeting? Conceptual, collaborations any papers or experiments.
It was almost universally mentioned that this was one of the best meetings most participants had attended in a long time. The format of not having a lot of data slides but having discussions was very successful. A number of discussions about collaborations going forward were also initiated.

What do you see developing in this field from this meeting?

  1. Better approaches for treating patients with genetic disorders of telomere maintenance
  2. New approaches to targeting telomerase and ALT cancers
  3. A better understanding of which cancers are the best candidates for telomere-based therapies

How does this impact patients today?
Several approaches to leverage the biology of telomeres are currently in clinical development so optimism is high that in the near future new approaches to treating patients with cancer will occur.

Venue & Travel Information

Hilton Denver Inverness

200 Inverness Drive West
Englewood, CO 80112

hilton.com
303-799-5800

Travel Forms

Travel forms are due 30 days prior to the start of the meeting to allow enough time to plan transportation.

Denver International Airport (DIA) is approximately 30 minutes from the meeting location.

  • Arrivals - Thursday around 1 PM, 3 PM and 5 PM
  • Departures - Sunday around 10 AM and 12 PM
TRAVEL FORMS DUE:
September 17, 2019
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.
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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.
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  • 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:
September 17, 2019
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.
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  • 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

Mary
Armanios
,
MD
Johns Hopkins Medical Institute
Stephen
Artandi
,
MD, PhD
Stanford University
Rene
Bernards
,
PhD
Netherlands Cancer Institute
Alison
Bertuch
,
MD, PhD
Baylor College of Medicine
Simon
Boulton
,
PhD
Francis Crick Institute UK
Rochelle
Buffenstein
,
PhD
Calico Lab
Carla Daniela
Robles-Espinoza
,
PhD
Intl. Lab for Human Genome Research, U. of Mexico
Roger
Greenberg
,
MD, PhD
Univeristy of Pennsylvania
Dirk
Hockenmeyer
,
PhD
University of California, Berkeley
Marcin
Imielinski
,
MD, PhD
Weill Cornell Medicine
Jan
Karlseder
,
PhD
The Salk Institute
Joachim
Lingner
,
Ecole Polytech Federale de Lausanne
Vicki
Lundbald
,
The Salk Institute
Roderick
O'Sullivan
,
PhD
University of Pittsburgth Medical Center
Sharon
Savage
,
MD
National Institutes of Health
Agnel
Sfeir
,
PhD
New York University

Forum Scholars

Floris Barthel, MD
The Jackson Laboratory for Genomic Medicine
Marta Markiewicz-Potoczny, PhD
National Institute of Health
Enzo Tedone, PhD
UT Southwestern
Tianpeng Zhang, PhD
University of Pennsylvania