Control ALT, Delete Cancer

Fully Funded - Thank You!

In summer 2016, SENS Research Foundation and lifespan.io launched a crowdfunding campaign to finance our search for drugs that can block ALT — a survival mechanism used by some of the deadliest cancers.

We are immensely grateful to the 547 donors who contributed a total of $72,002, smashing our $60,000 goal.

Many of our donors also sent us a photo of a friend or loved one whose life has been affected by, or lost to, cancer. See them all on our Faces of Cancer photo wall.

Although the campaign is over, there's still a lot to do before the diseases of old age are brought under medical control. Please consider donating to support our other projects, or subscribing to our newsletter to be the first to learn about upcoming campaigns.

Project Donors

$5,000+

Christophe Cornuejols
Glenn Tisdale

$1,000-$4,999

Michael Boocher
David Chambers
David Marcaccini
Michael Marye
Oge Nnadi
Dmitry Okolnikov
Guilherme Oliveira
Reason
John Roe
Matthew Smith
 
Nick Yeates

$100 - $999

Jean-Pierre Abello
Alen Akhabaev
Leroy Arellano
Cynthia Armstrong
Brian & Sabine Atkins
Thomas Klauset Aurdal
Michael Beasley
Rolf Bohme
Amutha Boominathan
Louis Burke
Romina Chanduvi
Nader Chehab
Lars Claussen
Jonathan Cole
Alex Corrigan
Paolo Costabel
Todd Cowing
Greg D'Agostino
Bo Dahlborg
Andrew Dapkiewicz
Yuri Deigin
Alena den Otter-Pastuskova
Maria do Socorro Silva
John Doe
Edward Duncan
Andrew England
Claudio Erba
Brian Fenton
Oliver Ferguson
Alan Rivail Silva Filho
Roshen Ganesh
Michael Geer
William Grunow
Mike Hädrich
Hayley Harrison
Adam Herrman
Douglas Hoch
Jappie Hoekstra
Amund Hov
Karel Hulec
Wuming Jiang
Gareth Johnson
Larry Johnson
Mike K.
Bernd Kalbfell
Håkon Skaarud Karlsen
Neil Kauffman
Pamela Keefe
Ken
Daria Khaltourina
Richard Kollen
Cynthia Kritikos
Guillaume Lastecoueres
Michael Livshits
John Lubaszka
David Luck
Ted Mann
Paul Marsh
Cam Marsollier
Michael
Miguel Ángel Moreno
Nicolas
Janette O'Halloran
Anthony Pulido
Nate Rifkin
Raoul Romano
Tree Rost
Haroldo Silva
Heli Simpson
Basil Singer
Peter Smit
Henrik Mathisen Sotnedal
Paul Spiegel
Stefan
Gennady Stolyarov II
Alexandre Strzyzewski
Ori Takemura
Curry Taylor
Steve Tebon
Paul Thacker
Simon Tost
Martin Towner
Pablo Varasa
Donovan Walker
Will Ware
Brandyn Webb
Robert Wilkes
Powell Wilson
Adrian Wolf
Arsen Zahray
Jeff Zaroyko
Dominic Zedan

$11 - $99

Fabio Albertario
Matthias Andre
Alexey Antonov
Brad Arnold
Nicola Bagalà
Vsevolod Barabanov
Corey Barcombe
Jillian Barfield
Jerri Barrett
Jan-Willem Bats
Alex Beckett
Barry Bentley
Graham Bentley
Myles Berdock
Dustin Biernacki
Karl Blasius
EdwinSue Boden
Judith Bongiovi
Kevin Brown
Mark Bruce
Sven Bulterijs
Christian Burger
Patrick Burgermeister
Melvin Burton
Jonty Bylos
Eugene Bystrak
Robert Campbell
Guilherme Campos
Ted Chapple
Yaniv Chen
Bryan Chisenhall
Ivan Cicanovski
James Clement
Michael Cole
Peter Colin
Brian Collins
Vincent Comito
Eric Conrad
Corbin
Carol Cortese
Franco Cortese
Anne Corwin
Walter Crompton
Wei Cui
Roger Davis
David Dayan
Gary Dean
Edouard Debonneuil
Dalibor den Otter
Karl Doerrer
Qais Muhammad Durani
Trent Eady
Eila
Miguel Ferro
Simon Fischer
Jeffrey Fisher
Robert Floto
Christina Freehauf
Ralph Friedman
Franz Fuchs
Timothy Gale
John Galterio
Birdie Gandy
Antonio Regidor García
Johan Giraldo
Zarathustra Goertzel
Grier Govorko
Kevin Graham
Dan Grecu
Christopher Greene
Sean Greene
Jean Marc Gruninger
Ruben Guazzelli
Elaine Halleck
David Halvorsen
Jens Christian Hansen
Jone Haugland
Rupert Hazle
Daniel Heard
André Heinonen
Austin Henderson
Nathan Henderson
Lukas Henschke
Richard Herrell
Alexander HighCat
Steve Hill
Fred Horan
Eva Hov
Magne Hov
Keith Hoyes
Adam Hruby
Tyler Hruby
Tracy Hughes
James Hutchison
Alice Hynes
Timothy C. Inzana
Daniel Izaguirre
Abraham Jaleel
Will Jarvis
Poul Martin Jensen
Joe
Ed Johnson
Eric Johnson
Matt Johnstone
James Joyce
Chelsea Just
Barış Kaya
Rosemary Kelly
Sadi Khan
Nicolai Kilian
Nikolay Kolev
Tom Lacy
William Lai
Alistair Lawson
Nathan Lefler
Jeremy Levy
Jamey Lewis
Christian Lindeblad
Kyle Litwin
Vlad Lopatin
Pedro Ivan Lopez
Mihkel Lukats
Jacob Mattison
Albert McCune
Shane McDonald
Patrick McHargue
Jonno Meindert
Teresa Mendez
Elena Milova
Bill Minor
Jason Morton-McKay
Adam Muntner
Thomas Murtagh
Josip Musac
Scott Nesbitt
Kai Chung Ng
Tiju O.
Thomas O'Brien
Matthew O'Connor
Martin O'Dea
Ziggy O'Reilly
Tony Otis
Tsimafei Padvitski
Anat Paskin-Cherniavsky
Paul Patras
Mary Patterson
Ian Paul
Piotr Pawlik
Adam Perrotta
Mark Philpott
Richard Piekut
Ben Plunkett
Dean Pomerleau
Robert Powles
Rosa Pozo
Edmond Pruteanu
Fabian Pudlo
Viviana Ramalho
Ferdinando Randisi
Michele Randisi
Toby Rane
Poonam Rashingkar
Brent Reitze
Darren Reynolds
Jessica Roberts
G.H.M. Roding
Oliver Rowland
Thomas Ruhm
David Saum
Eric Schulke
Hunter Secrest
Thomas Short
Alan Silva
Aline Silva
Matthew Simms
Selene Simonson
Deadly Smedley
Timothy Smerken
Rick Smith
Brian So
Peter Spriggs
Tim Steeman
Lucy Stewart
Alexandra Stolzing
Richard A. Sundvall
Sydnee
T. Thomas
Murray Thompson
Jay Tkachuk
Reuben Tracey
Benjamin Turner
Steven Tuttle
Graham Tyler
Christian Ubbesen
Luca Veronese
Dmitry Veselov
Marianne Vidojevic
Tom Vitasse
Gabriel Voicu
Aaron Vollrath
Oliver Ward
Christopher Wayland
David Wilkins
Mark Williams
Tom Wolk
Ian Wright
Daniel Yokomizo
 
Emily Young
Ben Zealley

$10

Gianluca Tabbita Bonifazi
Daniel Bostonweeks
Catalin Butiu
Jesse Campbell
Clivia Carneiro
Florian Cauvin
Didier Coeurnelle
Johnny Courmontagne
Robert Craven
Edmee de Klerk
Christopher DeVere
Pete Fewings
Guillaume Galdrat
Zackerie Galhardo
Jelle Geerts
Adam Gibbons
Marc Glesser
Andres Gomez-Emilsson
Calvin Goodman
Raymond Gough
Jordan Graves
S. Green
Mario Gruber
Celine-Lea Halioua-Haubold
Kohei Harada
Louie Helm
Nate Hill
Ted Howard
Jarrod Hunt
Matt Huson
Clément Izard
Martyn James
Gareth John
Carl Kenner
Christian Kerner
John Kirk
Tommy S. Kjær
Martin Kleman
Alejandro Kondrasky
Kim Lindholm
Andrew Raphael Łukasik
Lukas Macijauskas
Kelly Martin
Chris McAulay
Eric Meger
Martijn Meijer
Máùrícè Mullenders
Mikael Murstam
Otto Normal
Michał Nowakiewicz
Vincenzo Paduano
Estelle Perry
Daniele Piersanti
Richy Pops
Brandon Porter
Janet Ransom
Josh Russell
Daniel Sacilotto
Roland Scheidel
Elliott Scholes
Derek Scholl
Yuriy Sherayzen
Grant Simmons
Lasse Simonen
Frank Smith
Theresa Staunstrup
Martin Šulák
Andreas Svanoe
Jamin Szczesny
Grant Takara
Carl Tasios
Transhuman Tees
Roshawn Terrell
Carlie Thompson
Tio
Evyn Tyndzik
Otto Valtakoski
John van Dijk
Ekaterinya Vladinakova
Tyler Vo
Marcus Watts
Deane Williams
Lawrence Witt
William Yang
Martin Zealley
 
 
Chris Zoumadakis

Control ALT, Delete Cancer Project Description

Learn more about the team behind Control ALT, Delete Cancer in this virtual reality tour of SRF's Research Center in Mountain View, California, led by Dr. Aubrey de Grey.

Of all the risk factors associated with cancer: obesity, smoking, sun exposure etc., there is none more universal than aging. According to a 2011 report on Global Health and Aging, the number of people aged 65 or older is projected to reach 1.5 billion by 2050 and correspondingly the yearly number of new cancer cases alone is estimated to reach 27 million by 2030. Therefore it is of paramount importance to develop new anti-cancer approaches to meet the humanitarian and economic challenges associated with our aging global population.

One such approach is to target cancers that employ a particular mechanism to achieve cellular immortality — Alternative Lengthening of Telomeres, or "ALT".

What is ALT?

Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called telomeres, gets shorter. When the telomeres shorten too much, the cell permanently stops dividing and either enters senescence or undergoes apoptosis (programmed cell death). Telomere shortening thus acts as a biological mechanism for limiting cellular life span. Most cancer cells bypass this failsafe by synthesizing new telomeres using the enzyme telomerase.

Several therapies targeting this well-described telomerase-based pathway are in the advanced stages of clinical development, but as with any cancer therapy there is the potential for development of resistance against telomerase-based strategies to defeat cancer. Studies using mice and human cancer cell lines have demonstrated that cancer can overcome the loss of telomerase by using a telomerase-independent mechanism called alternative lengthening of telomeres (ALT). Furthermore, existing tumor cells in mice have also been observed to switch over to the ALT pathway as a result of telomerase-inhibiting treatment. It is therefore plausible that telomerase-dependent cancer treatments will introduce selective pressures in human tumors to activate the ALT pathway and/or select for cells already using ALT within the tumor. This makes the development of ALT-specific therapies imperative for the success of complete anti-cancer approaches.

There are currently no ALT-targeted anti-cancer therapeutics, however, largely because this process is much less well understood. In contrast to telomerase-driven telomere lengthening, which does occur in the stem cells of healthy tissues and organs, ALT activity is not found in normal human postnatal tissues. A positive side of this fact is that this would allow for more-effective dosing with minimal side effects. ALT is present in some of the most clinically challenging cancers to treat, such as pediatric and adult brain cancers, soft tissue sarcoma, osteosarcoma, and lung cancers. Clearly, targeting ALT is a very attractive strategy in the development of novel cancer therapies.

Edward James Olmos describes the relationship between telomeres and cancer

How we will target ALT-based cancers

Unlike the telomerase pathway, the precise enzymatic details of the ALT mechanism are not yet well understood. The presence of ALT activity has often been inferred from detecting telomere-related phenotypes, such as long and heterogeneous telomere length distributions or ALT-associated promyelocytic leukemia nuclear bodies (APB), which indicate the abnormal presence of telomeres inside a complex formed from otherwise ubiquitous nuclear proteins. These markers are not entirely satisfactory, as they can sometimes yield inaccurate results and are not practical for high-throughput applications or clinical laboratories.

A key step towards the development of ALT-targeted cancer therapeutics and diagnostics was the discovery of the first ALT-specific molecule, the telomeric C-circle, by our collaborator, Dr. Jeremy Henson, back in 2009. C-circles are an unusual type of circular DNAs that are created from telomeres. The level of C-circles in cancer cells accurately reflects the level of ALT activity, and this biomarker can be found in the blood of patients who have bone cancers positive for ALT activity. The OncoSENS research team at the SENS Research Foundation, in collaboration with Dr. Jeremy Henson at the University of New South Wales in Australia, has developed a novel version of the C-circle assay that can be fully automated using robotic liquid handlers, making it now feasible to perform robust high-throughput screenings to search for chemical modulators of the ALT pathway. The project workflow is detailed in the figure below:

OncoSENS workflow

Goals

The goal of this project is to screen a library of about 115,000 compounds containing structurally diverse, medicinally active, and cell permeable drugs from a variety of fields of medicine (oncology, cardiology, and immunology, etc.), for inhibitors of the ALT pathway. The crucial advantage of making use of such drug libraries, which are richly documented and contain some FDA approved compounds, is that once hits are identified and validated using our ALT-specific assays they can potentially be repurposed for the treatment of patients with ALT cancers through cheaper, faster and safer preclinical and clinical validation protocols. Our initial goal of $60,000 will allow us to test a significant subgroup of this library, and reaching a stretch goal of $200,000 will allow us to test them all.

Donor rewards include exclusive SRF merchandise as
well as private meetings with the OncoSENS team,
Dr. de Grey, and even legendary actor Edward James Olmos!

The human ALT cancer line U2OS will be used in all experiments. This cell line was derived from a patient with osteosarcoma that was positive for ALT activity already and is commonly used in the literature. These cells will be cultured in media containing several different concentrations of the drugs in the library in a multi-well high-throughput screening (HTS) format. Genomic DNA will be extracted from these cells and these samples will be processed for the HTS C-circle assay especially developed by our team using a fluorescence-based method. Analysis of the changes in these fluorescence signals will allow us to identify compounds that most efficiently reduce C-circle levels and thus significantly inhibit the ALT pathway.

We will also be able to identify the concentration at which this inhibitory effect is maximal by testing these compounds at a variety of concentrations spanning different orders of magnitude. The C-circle signal will be normalized by the amount of genomic DNA present in each sample by using a commercially available dye that binds double-stranded DNA specifically. These data can also be correlated with cell viability for each drug.

Based on the conservative estimate that 10 percent of cancers employ an ALT strategy to achieve cellular immortality, there are about 1.4 million new cases and 820,000 deaths globally due to ALT cancers every year. We expect these numbers to at least double by 2030 as the world’s population ages and telomerase-based anticancer therapies gain approval to treat cancer patients. Therefore, the development of ALT-targeted therapies is critically needed in the fight against aging and cancer.

Please help us control ALT and thus delete the burden of cancer from society at large.

Thank You.