Non-genetic Drug Tolerance Mechanisms
Forum Chairs
Forum Description
Despite a favorable initial response to therapy, a third of cancer patients will develop recurrent disease and succumb within five years of diagnosis. It is widely accepted that relapse can be driven by genetic mutations that were either pre-existing or arose de-novo during drug treatment. Over the last decade a rare subpopulation of cells, termed cancer persister cells, have been identified as orthogonal drivers of treatment failure. Unlike resistant cells that harbor a genetic alteration that enables them to survive and expand in the presence of a drug, persister cells are transiently drug-tolerant cells that can survive exposure to therapy through reversible, non-mutational mechanisms. The nascent field of cancer persistence has expanded rapidly since the first cancer persister system was reported 12 years ago. Initially described in the context of targeted therapy, drug-tolerant cancer cells have since been implicated in disease recurrence in multiple cancer models and in response to a diverse array of treatments.
This Forbeck forum will provide a unique opportunity for investigators from around the world who are working on this newly emerging field in cancer to gather, discuss, and critically examine emerging concepts in the field of cancer persisters. We will start with understanding molecular mechanisms of cancer persistence and will continue with discovering therapeutic targets of persistent cells, deciphering their heterogeneity at single cell level, learning how cancer persisters differ from microbial persisters, modeling of the dynamics of persistent cells, and identifying contribution of immune escape mechanisms in driving cancer persisters. This meeting will bring together researchers who study non-genetic drug tolerance in various contexts and who are not used to interacting with each other to discuss key questions in the field and lay the foundations for generating a community dedicated for the study of nongenetic tolerance/resistance. We anticipate that this will result in potential collaborative projects, ideas for sharing the concepts discussed in the meeting with the greater scientific community through publications, and aspirations for future follow-up meetings focused at this exciting emerging field.
The most important factor that limits the success of anti-cancer therapy is the emergence of drug resistance; for instance, median survival of 30-36 months with vemurafenib in BRAFmutant melanoma yet > 1/3rd of patients die within 2 years. Until recently, most of the studies to date (as well as most conferences) were focused on studying the contribution of genetic mechanisms of evolution in drug resistance. However, we seem to have reached a limit in terms of characterizing genetic mutations that give rise to acquired resistance across multiple cancer types. It has become clear from numerous lines of recent evidence that beyond genetics, nongenetic/functional mechanisms that also contribute to resistance development. Similar to bacterial cells in response to antibiotic resistance, cancer cells also acquire a persister state to escape drug pressure. The emergence of persister population can occur via different mechanisms including epigenetic plasticity, metabolic reprogramming, itochondrial unpriming, immune escape, and others at bulk and single-cell levels. Despite important similarities in, and differences between, mechanisms of drug tolerance in bacteria and in cancer cells, few opportunities exist for leaders in these two related fields to interact in a meaningful way. Therefore, this meeting could provide a unique opportunity to gather experts working on microbial and cancer persistence, to define phenotypes, emergent mechanisms, and targeting strategies to overcome non-genetic resistance mechanisms.
The goal of this meeting is to bring together experts from fields of epigenetics, metabolism, single cell omics and microbial and cancer persisters fields to facilitate the discussion to define the functional phenotype of cancer persisters, discuss innovative models to study persisters, and devise novel strategies to target this rare minimal disease (MRD)like cells. By bringing clinicians and translational biologists together, we hope to come up with studies that can provide strong clinical evidence of the xistence of persister population across different tumor types and discuss ways to target it to prevent disease recurrence. This meeting will bring together biologists, bacteriologists, translational scientists, and clinicians to discuss emerging concepts in the non-genetic cancer resistance field and lay the foundation for a cohesive framework to study them. This meeting will provide a unique opportunity to create the intellectual infrastructure and common ground that is needed to propel the field forward. For the first time, this forum will also provide a unique opportunity to bring together scientists from cancer persistence and microbial persistence fields and enable interdisciplinary discussions on how lessons from antimicrobial resistance can help to study and conceptualize cancer persisters.
Important program Note
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Sponsoring a Forbeck Forum is a powerful way to directly support groundbreaking cancer research by fostering collaboration among top scientists in the field. These intimate, focused meetings bring together leading researchers to share ideas, challenge assumptions, and spark innovative approaches that can accelerate progress toward cures. Your sponsorship helps cover the cost of hosting these unique gatherings, ensuring that vital conversations and partnerships continue to thrive. It's an investment in science, in collaboration, and ultimately, in better outcomes for patients.
Forum Summary
Forum Summary: Non-Genetic DrugTolerance Mechanisms
The Forbeck Foundation supported a groundbreaking forum on "Non-Genetic Drug Tolerance Mechanisms" held at Castello dal Pozzo, Oleggio Castello, Italy. This forum brought together an international group of leading scientists and clinicians to address one of the most pressing challenges in cancer therapy: the emergence of drug-tolerant persister cells that drive treatment failure through non-genetic mechanisms.
The forum opened with a comprehensive examination of cancer persister models in session I. Dr. Shruti Bhatt presented compelling work on modeling and targeting drug-tolerant persisters in acute myeloid leukemia, highlighting how these rare sub-populations survive chemotherapy through reversible, non-mutational mechanisms. Dr. Aaron Hata explored therapy-induced APOBEC3A, demonstrating how the traditional boundaries between drug tolerance and resistance are increasingly blurred as cells transition between these states. Dr. Catherine O'Brien contributed insights into the molecular foundations of persister cell biology, while Dr. Yogesh Goyal (Forbeck Scholar) presented innovative single-cell approaches to trace decision-making processes in individual cancer cells upon drug exposure. The session concluded with Dr. Mark Dawson's presentation on both genetic and non-genetic mechanisms of clonal fitness, providing a comprehensive framework for understanding how cancer cells adapt to therapeutic pressure.
Session II: Non-Genetic Mechanisms of Persister Evolution delved deep into the molecular mechanisms underlying persister cell evolution. Dr. Matthew Hangauer revealed a novel role for the apoptotic DNase CAD/DFFB in suppressing interferon signaling, contributing to acquired drug resistance. Dr. Arjun Raj provided insights into the stochastic nature of cellular decision-making in drug tolerance, while Dr. Chad Pecot demonstrated how tumors remodel themselves to overcome dual KRAS/MYC inhibition. Dr. Eran Hodis (Forbeck Scholar) presented his search for missing causes of non-genetic drug resistance in melanoma, revealing previously unrecognized pathways. Dr. Mariangela Russo concluded the session by discussing cancer persister cells from the perspective of adaptive mutability and identifying clinical opportunities for intervention.
A unique aspect of this forum was the integration of microbial and cancer persistence research. In Session III:Microbial Models of Persisters, Dr. Kim Lewis, leading microbiologist, set the foundational insights into bacterial persister cell formation mechanisms, providing crucial parallels for understanding cancer persistence. Dr.Sabrina Spencer explored the critical processes of cell-cycle withdrawal and re-entry under both targeted and chemotherapy, revealing fundamental principles shared across biological systems. Dr. A-Rum Kim (Forbeck Scholar) presented work on EZH2-targeted therapy in hepatocellular carcinoma and strategies to reverse drug resistance. Dr. Kris Wood discussed mechanism-based dependencies in residual cancers, while Dr. Adam Wolpaw examined neuroblastoma through the lens of lineage states and persister states, particularly focusing on MYCN's role in these processes.
The final session on Therapeutic Targeting of Cancer Persisters focused on translating basic insights into therapeutic strategies. Dr. Anthony Letai provided a comparative analysis of similarities and differences among persister cells of diverse origins, establishing fundamental principles for targeting these populations. Dr. Doug Green presented fascinating work on "Flatliners" -near-death experiences in cancer cells - revealing how cells survive extreme stress conditions. Dr. Caroline Robert discussed translational regulation of biomarkers in drug-tolerant persistent melanoma cells in human patients, examining correlations with tumor microenvironment and treatment response. Dr. Sydney Shaffer contributed insights into the heterogeneity of persister populations, while Dr. Joan Brugge concluded the forum with comprehensive analysis of ovarian cancer heterogeneity and cellular programs associated with chemotherapy tolerance.
Key Achievements and Impact
This forum addressed a critical gap in cancer research by bringing together experts studying non-genetic drug tolerance mechanisms - a field that, while emerging and challenging to fund, represents some of the most cutting-edge work in cancer biology today. The intimate setting fostered unprecedented cross-disciplinary collaboration between cancer biologists, microbiologists, and clinicians.
Major outcomes included:
- Conceptual Framework Development: Participants established a cohesive framework for studying cancer persister cells, defining key phenotypes and identifying shared mechanisms across different cancer types.
- Interdisciplinary Insights: The unique integration of microbial and cancer persistence research revealed fundamental principles that span biological systems, offering new therapeutic strategies informed by antimicrobial resistance research.
- Clinical Translation Pathways: The forum identified concrete opportunities to translate basic discoveries into clinical applications, including biomarker development and combination therapy strategies
- Collaborative Network Formation:The meeting established lasting partnerships among investigators who rarely interact despite working on related problems, creating a foundation for future collaborative research.
The forum's impact was clearly reflected in participant feedback:
- "This was a great meeting, I enjoyed it more than any meeting in the last two years maybe more. I think it is also a tribute to the format."
- "Our community for persisters in cancer therapy has flourished, and we owe a significant debt of gratitude to Forbeck for their invaluable support in making this possible."
- "This Forbeck meeting was outstanding. The quality of scientists assembled, and their diversity of interests, made it to be a special and productive meeting for cross-fertilization of ideas. I am certain it will result in future collaborations and new directions. It is certainly among the best meetings I have attended, and whoever selected the scientists for this meeting really has their finger on the pulse of who is a thought leader in this field."
Future Directions and Significance
This Forbeck Forum successfully brought together thought leaders in an emerging field critical to cancer treatment success. The non-genetic drug tolerance mechanisms field, while challenging to fund and study, represents one of the most promising frontiers in cancer research. The meeting's emphasis on both bacterial and cancer persistence models proved particularly valuable, revealing evolutionary conserved mechanisms that can inform therapeutic development. The forum's success in fostering collaboration, generating new ideas, and establishing a cohesive research framework positions this community to make significant advances in understanding and targeting cancer persister cells.
The Forbeck Foundation's support of this forum demonstrates its commitment to nurturing emerging fields with transformative potential. As participants noted, this gathering will undoubtedly result in new collaborative projects, innovative research directions, and ultimately, better outcomes for cancer patients facing treatment resistance.
Venue & Travel Information
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Travel Forms
Please familiarize yourself with our travel policy below before booking your travel. If you have any questions about our policy, please do not hesitate to contact us for clarification.
Travel forms are due 30 days prior to the start of the forum. We cannot guarantee accommodation or airport transfer if this is not received in time.
AIRPORT TRANSFER INFORMATION
The Foundation will only provide pickups from Malpensa Airport (MXP) around the designated times below. Shuttle times may adjust slightly.
- Arrival day of the forum at approximately 9:00 AM, 1:00 PM, 3:00 PM and 5:00 PM local time
- Departures from the venue at approximately 6:00 AM, 10:00 AM, and 12:00 PM local time
The Foundation can only provide ground transportation to and from MXP on the arrival day and departure day. If you are arriving or departing outside those times you will need to arrange your own transportation to the venue.
HOTEL BOOKINGS & INFORMATION
The Foundation will only book hotel rooms for the duration of the forum. This is comprised of 3 nights (arrival day, forum day 1, and forum day 2). If you wish to arrive 1 day before the meeting due to jet lag or travel times, we will work with you on a case-by-case basis. For any extended stays before or after the meeting, you are responsible to book and pay for your own accommodation.
IMPORTANT INFORMATION ABOUT GROUND TRANSPORTATION
To maximize funding for our Forums, the Foundation does not reimburse ground transportation costs outside the designated shuttle pick-up times. If you arrive after the final shuttle, or do not wish to wait for or take a scheduled shuttle, you will be responsible for arranging and covering your own transportation to the Forum venue.
Travel Policy & General Information
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. So please note what we do and do not cover.
What the Foundation Pays For
- ACCOMMODATIONS for the nights of the Forum only. People traveling from oversees or far away may arrive 1 night early to adjust for jet lag or to navigate longer travel times.
- MEALS are provided by the foundation during the forum.
- A TRAVEL ALLOWANCE FOR AIRFARE will be set based on an economy ticket from your home airport. If you have travel before or after that is fine. We do not increase the allowance for other travel plans.
- The Foundation provides SHUTTLES TO/FROM THE AIRPORT to the meeting venue at designated shuttle times.
- You can select not to utilize Foundation arranged transportation at your own expense when completing the travel form.
What the Foundation does not cover
- We do not cover upgrades of any kind.
- Travel Allowance will not be increased due to late booking or changes.
- We do not cover incidental costs during your travel. So please do not send your food receipts.
- We do not cover additional nights at the venue outside of the meeting dates.
- We do not cover transportation outside of the designated shuttle times.
- We do not reimburse for home side airport transfer (to/from your home/office to your airport).
Important Things to Note
- Everyone must fill out the travel form!
- We must have your itinerary and travel receipt to receive reimbursement.
- Flights must be booked at least 30 days prior to the meeting or you may not have accommodations and airport transfer.
- We often use volunteers for airport transfers.
- The travel confirmation will be sent out the WEEK before your Forum.
- The speaking agenda will be spent out the NIGHT before your Forum.
- We expect participants to attend ALL sessions.
Frequently Asked Questions
- Travel Confirmation will be sent out with in 1 week of the meeting. This will include a hotel confirmation number, if there is one, airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Also due to frequent airline changes we wait until the week of the meeting to send this out.
- 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.
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.
Forum Structure
The structure of the forum 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.
- Each presentation is limited to 2 slide equivalents. Slides should include no more than one graph or gel per slide and a maximum of 5 bullet points. Avoid animations or motion effects. Slides should support discussion, not serve as a script. Thank you for adhering to the spirit of this format.
- A Whiteboard and markers will be available to supplement your digital slides.
- Everyone is expected to actively participate in every session and discussions.
- The time spent at the forum is relatively short, so please be familiar with papers received prior to arrival.
- It is very important that you commit to all sessions of the 2 days of the forum.
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.
Program
The schedule below outlines the official program for this forum. A detailed agenda, including individual speaking times, will be provided on the first day of the event.
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 forum. 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 forum.
- 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.
- 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
Forum Scholars
PODCAST
