Galien Golden Jubilee Forum USA 2021

PANEL 5
Oct. 28th, 2021
3PM – 4:15PM


Chairs:
Laurie Glimcher, President & CEO, Dana-Farber Cancer Institute

Panelists:
Scott Armstrong, President, Boston Children’s Cancer & Blood Disorders Center; Chairman, Department of Pediatric Oncology, Dana-Farber Cancer Institute
Danny Bar-Zohar, Global Head of Development, Merck KGaA
Giovanni Caforio, Chairman & CEO, Bristol Myers Squibb
Samit Hirawat, Executive Vice President, Chief Medical Officer, Global Drug Development, Bristol Myers Squibb
William Kaelin, Sidney Farber Professor of Medicine, Harvard Medical School and Dana-Farber Cancer Institute
Crystal Mackall, Ernest & Amelia Gallo Family Professor of Pediatrics & Internal Medicine, Stanford University

PANELIST BIOSFULL PROGRAM

New breakthroughs in the biology of cancer: Pioneering novel ways to enhance and restore the body’s ability to fight cancer


Driven by increased understanding of the biology behind cancerous cell growth and suppression, oncology has emerged as the most productive source of new breakthroughs in medicines research.   Industry analyst IQVIA forecasts that by 2025 nearly 100 new treatments will be added to the therapeutic arsenal for patients, pushing annual global revenues for cancer drugs close to the $300bn mark – and solidifying oncology’s current position as the single largest therapeutic category in pharma by sales.

In addition, 21 of the 53 novel drugs authorized in 2020 by the US FDA for clinical use in patients were for cancer indications.  The list includes breakthrough drugs for two rare pediatric cancers, neuroblastoma and neurofibromatosis; nine drugs for NSCLC, mostly novel immunotherapies, and others for cancers of the breast, colon, bladder, and gastrointestinal tract; the first liquid biopsy next generation sequencing (NGS) test as an aid to precision medicine; two self-administered drugs in tablet form for rare blood cancers, replacing costly in-office infusions; and a new combination drug formula developed from older medicines to treat mesothelioma in the lung.

In the years ahead, researchers are poised to benefit from advances in computational science capable of generating enormous volumes of human data.  Tools like NGS and liquid biopsy will offer still more insights into the tumor micro-environment, including the mechanisms that activate tumor growth and suppression.  The Human Cell Atlas Consortium, launched in 2016 to map and define all cell types found in the body, is gradually revealing how patterns in gene expression and physiological states within single cells impact malignancies in organs ranging from the bloodstream to the brain.

In short, the number of known molecules that can be targeted for development as cancer medicines is destined to grow exponentially. Identifying disease markers and gene signatures will allow for a direct view of human biology without the distortions from controlled cell cultures. The challenge is refining and adapting these new technologies to fit each patient’s disease profile, through the collaborative inter-disciplinary process known as precision medicine.

Panel Objectives

The focus of today’s panel is on three of the most promising – yet challenging – areas of cancer discovery and development research. These are:

Epigenetics and pediatric cancers

Pediatric cancers have benefited from some major clinical breakthroughs over the past three decades, particularly in the hematology space, but overall child survival rates lag the general cancer population and the long-term effects of therapy means that damaging cancer-related morbidities often persist well into adulthood.  What is needed is more targeted and less toxic treatments, driven by improved understanding of the special characteristics of drug resistance in children as they develop.

A key pathway to this destination is through the study of epigenetics, which addresses non-genetic developmental and behavioral changes that can influence how genes work in delivering their instructional blueprint for the body. Many pediatric cancers differ in that the causative factor is not a gene mutation but a simple error in development – linked to age, or even an infection – that ends up changing the expression of a gene as interpreted by the body’s own workhorse contingent of proteins and cells. Unlike genetic changes, epigenetic changes are easily reversible; while it cannot change an individual’s own DNA sequence, epigenetics can change how the sequence is read by cells and proteins in carrying out those genetic instructions.

All this makes epigenetics an important vehicle for influencing the initiation and progression of many childhood cancers, with most current investigations focusing on three inter-related biological processes that can induce carcinogenesis:  DNA methylation, histone protein modification and non-coding RNA regulation – the latter of which is now seen by researchers as an especially robust link in driving the cellular aberrations that can lead to malignancies.

Several novel drug therapies targeting these epigenetic alterations that suppress the anti-cancer immune response in children have recently entered clinical trials, a positive development that the panel will discuss. In addition, preventive measures, led by stronger diagnostics, are critical to progress in fighting pediatric cancer.  Many such cancers, including glioma of the brain, are especially deadly in children because they are hard to detect.  Optimism is growing that epigenetics research will eventually generate the tools to treat children with these rare cancers at an earlier stage, increasing the odds of survival.

Targeted protein degradation

Proteins, large molecules that fuel the basic work of cells and serve a crucial role as antibodies against disease, are an increasing target of cancer researchers as more is known about how some proteins help facilitate malignant tumor formation and metastasis.   An important new area of investigation is leveraging the improvements in understanding cell biology to create a new class of oral, small molecule drugs called protein degraders. These bind to a cancer-causing protein in ways that conventional antibodies cannot, allowing for the destruction of the protein’s functionality for malignant cell growth and proliferation.

Protein degraders are now being tested in trials to address many longstanding issues in cancer biology, including tumor targets once thought “undruggable;” overcoming common chemical resistance mechanisms; and gaining deeper biologic insights into how proteins influence the onset of disease in many areas, not just cancer. At the forefront are a group of compounds known as PROteolysis Targeting Chimeras (PROTACs); another similar, cohort called molecular glues eliminates cancer-causing activity by “hijacking” the aberrant protein and forcing it to interact with another protein in ways that degrade its carcinogenic properties.  Guiding this research is an expanding array of clinical best practice guidelines, reagents, assays and computational technologies that will help direct and shape future progress in this field.

The panel will examine the status of protein degraders in moving forward to regulatory approval and eventual use in the clinical setting.  According to recent reports in Nature and other scientific journals, as many as 15 of these new therapeutic modalities could reach that patient-friendly milestone by early next year.

Advances in Immunotherapies     

The biggest single trend in cancer care in the last decade has been the arrival of cancer immunologic drugs designed and administered with the individual patient in mind.  Now the push is on to improve the efficacy and durability of these drugs:  while the industry has commercialized more than 60 immunotherapy drugs since 2014, the majority of cancer patients – particularly those with solid tumors – fail to achieve lasting results due to some severe side-effects and the ability of cancer cells to develop resistance to the accelerated immune response.

However, evidence is growing that using these drugs in combinations with other agents like chemotherapy and immune agonists are improving the odds for patients. Many such combinations, along with a new wave of companion diagnostics, are presently in various stages of review by the FDA and are likely to win market authorization over the next two years.

Progress is also evident in solving for the major genetic mutations that predispose patients to different types of cancers, including those most resistant to conventional treatments such as the KRAS, BRAF and PD-1/PD-L1 mutations.   For example, KRAS gene mutations are present in a quarter of all cancers diagnosed today.   Researchers first identified KRAS mutation 40 years ago but only in the last few months has a viable, multi-target therapy reached patients.

The CAR-T class of cellular therapeutics, first introduced for clinical use in 2017, is offering potential new pathways beyond its initial success in treating blood- based cancers. Reliance on CAR-T to fight the solid tumors that typify most cancers (almost 90% of cases) is likely to become a clinical reality within the next two years, expanding the number of cancer patients who can benefit.

There is also promise in refinement of the CAR-T platform with the arrival of CAR-NK (natural killer) cellular therapy that offers advantages like the feasibility of allogeneic “off the shelf” manufacturing, along with a much lower risk of cytokine release syndrome in patients. It’s also much easier compared to the current autologous process of trying to re-engineer a sick patients own T-cells in a controlled lab setting.  In addition, new research is demonstrating that CAR-T therapy could be a tool in fighting some deadly pediatric cancers that elude treatment by conventional means.

Research is also advancing in producing a therapeutic “off” switch to the actions of certain proteins that orchestrate the “exhaustion” of immune system T-cells, which serve as the frontline in seeking out and eliminating specific cancer-causing antigens.  Trial studies now underway are likely to confirm that a class known as protein transcription factors induce T-cell exhaustion in patients with cancer. The finding will result in new, better approaches to boosting the effectiveness of immunotherapies in a wide range of cancers.

Overall, the narrative driving cancer research is the increased options that patients will have as technology and science combine to open new pathways to treat, if not cure, conditions that once amounted to a death sentence.  Such options count even more as awareness grows that cancer is not one disease but a series of small, rare conditions that are mostly genetic in origin.  Understanding each patient’s disease profile is critical to a successful clinical outcome, which will be assisted by greater physician reliance on stratified biomarkers to determine the appropriate therapies.