“The First Cell” is the title of a revolutionary book written in 2019 by oncologist Azra Raza from the Columbia University Medical Center. In it, she calls for a radical shift in cancer funding away from its current predominant focus on late stage treatments, and towards early detection of what she calls “the first cells.”
Shortly thereafter, a group of noted dignitaries in the field collectively called The Oncology Think Tank convened to begin hashing out this new imperative, and then bring it to fruition. In the popular magazine Scientific American, the group recently published their vision for a future when no cancer will be detected too late to treat.
The logical entry point into this path begins with the most important resource now available – extant cancer survivors.
I recently spoke with Azra about her plans to establish The First Cell Center for Cancer Survivors (FICCCS), and asked her to provide a summary for us of how it might work.
She said: “There is a crisis in oncology. Cost of cancer care will consume more than 80% of cancer spending by 2030. Only 6% of cancer drugs approved between 2006–2017 showed meaningful, measurable, quality of life improvements while a good 70% show 0% improvement in survival.
Twenty years after the human genome was sequenced, and despite an overwhelming focus on gene-centric research, very little has changed for the cancer patient.
Yes, we are curing 68% of newly diagnosed cancers, but curing with what?
The same slash-poison-burn strategies. And the outcome for the 30% we are not curing, because they present with advanced disease, is no different in 2021 than it was in 1930.
“Trying to treat end-stage cancer with targeted therapies is like taking a heart destroyed by infarction and trying to fix it with a coronary artery bypass. It is clear that the only successful strategy in any disease is early detection, and better still, prevention. It is time to apply this age-old formula to cancer.
“How early is early? The earliest possible stage, at inception, in fact, at the First Cell stage. The problem is that cancer is a silent killer. Even the earliest Stage 1 tumors contain millions of cells.
How do we find the First Cell? The answer is simple: By monitoring individuals at high risk of developing cancer for the appearance of the First Cell. Who are these individuals?
“There are many such groups. Individuals with hereditary predispositions (Li Fraumeni syndrome, Lynch syndrome, mutations is BRCA1/2, heavy smokers). Another distinct group is individuals with a history of cancer. In fact, one in five new cancers occurs in a cancer survivor.
Due to their ongoing need for follow-up care, cancer survivors are already connected with the healthcare systems. They have detailed medical records available. They come every six months for a regular check-up to the clinic anyway. It would be feasible to monitor them and collect biospecimens on a regular basis.
This group offers us the best chance of trapping the First Cell. We propose to establish The First Cell Center for Cancer Survivors (FICCCS) to study this group.
“We propose to obtain non-invasive samples of blood, saliva, urine and feces twice a year from the cancer survivors. Part of the blood will be passed through a filter technology to trap the First Cells on the basis of size (they are giant cells), and the rest for bio-marker and multi-omic studies.
“If two institutions (Columbia and Hopkins or MD Anderson) contribute samples on 2000 cancer survivors each per year, in three years, we will have 12,000 unique subjects. It is calculated that 507 will develop a new cancer in this period. This is a huge number and will provide a plethora of information on the foot-prints of the earliest disease including biomarkers and The First Cell trapped on filters.”
Taking the next steps
Azra notes that a center such as this could be established on a modest budget of $1M/year for the first few years. Presumably, other institutions would follow on the heels of these initial efforts. In a recent interview for Aga Khan University as part of their Special Lecture series, Azra explores some of the cutting-edge research that can help make this all happen.
While many fancy new technologies are now available for tracking populations of cells in vivo, they are often applied too late in the cancer cycle to be of any real value to the patients.
For example, we recently explored the Tapestri single-cell tracking platform developed by Mission Bio for exploring clonal populations of hemapoetic cells in acute myeloid leukemia (AML). We also recently investigated new technologies for single-cell imaging of the micrometabolic state of heterogenous cancer cells.
Unfortunately, most of the critical patients currently getting access to these technologies are mice, not humans. Furthermore, they are mice that already have well-developed tumors that bear little resemblance to resistant cancer cells that emerge in humans who have already relapsed after chemotherapy.
There is still a lot of institutional inertia to overcome before fully implementing large-scale First Cell detection for every man and woman. However, as cancer survival centers in the form mentioned above are established, we can expect this inevitable transformation to take hold.
Cancer is one of the leading causes of mortality worldwide.1,2 Opportunities to help reduce the death rate from cancer through the discovery of new drugs are benefiting from the increasing advances in technology and enhanced knowledge of human neoplastic disease.3,4 However, translation of these new drugs into clinical practice has been far slower than expected.5,6
Drug development requires an average of 13 years research. In addition to design and production, it is necessary to examine the efficacy, toxicity, and pharmacokinetic and pharmacodynamic profiles of the drug in cell- and animal-based studies.7,8 Bringing a single new drug from bench to bedside is expensive, with costs of bringing a new chemical entity to market being estimated at ~USD2–3 billion.9,10
A key step in drug development is testing the safety and efficacy in human subjects in clinical trials that normally comprise four phases.11
Phase I clinical trials test the new drug for the first time in a small group of people (e.g., 20–80) to evaluate safety (e.g., to determine a safe dosage range and identify side effects).
Phase II clinical trials study intervention in a larger cohort (several hundred) to determine efficacy and to further evaluate drug safety.
In phase III studies efficacy is then studied in large groups of trial participants (from several hundred to several thousand) comparing the new intervention to other standard or experimental interventions (or to non-interventional standard care). Phase III studies also monitors adverse effects and collects further information that will allow the intervention to be used safely.
Phase IV studies occur after the drug has been marketed. These studies are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use over longer periods of time. In general, if the drug is found efficacious in Phase III trials, it receives FDA approval. However, only one of every 5000–10,000 prospective anticancer agents receives FDA approval and only 5% of oncology drugs entering Phase I clinical trials are ultimately approved.12,13 Recently, the escalating cost and timeline required for new drug development means that if drug resistance arises, patients with advanced disease may die before alternative treatments become available.14,15
Drug repurposing (alternatively called “new uses for old drugs”) is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication.16,17 Increasingly, researchers and clinicians are considering this strategy to alleviate the dilemma of drug shortage for finding new cancer therapies.18
The major advantage of this approach is that the pharmacokinetic, pharmacodynamic, and toxicity profiles of drugs have been already established in the original preclinical and Phase I studies. These drugs could therefore be rapidly progressed into Phase II and Phase III clinical studies and the associated development cost could be significantly reduced.10,19 Thus, drug repurposing holds the potential to result in a less risky business plan with lower associated development costs, especially if failures of new drugs during research and development (R&D) are factored in (Fig. (Fig.11).20,21
The estimated time and main steps in de novo drug discovery and development and drug repurposing for cancer therapy. De novo drug discovery and development for cancer therapy takes 10–17 years and comprises basic discovery, drug design, in vitro and in vivo experimentation (including identifying safety and efficacy), clinical trials and finally drug registration into the market. In contrast, drug repurposing for cancer therapy takes only 3–9 years as it can bypass several processes that have been completed for the original indication if the anticancer potential of the candidates is confirmed
In recent years, advanced genomic and proteomic technologies for the assessment of cancer specific biological pathways leading to new drug targets has escalated.22–24 This provides excellent opportunities for drug repurposing.25 Almost all drugs used in human therapy have the potential to address more than one target.22,26
Thus, if the targets of these drugs are highly consistent with cancer, there is a high likelihood that those which share common targets could be therapeutic for other cancer patients.27,28 However, drug repurposing historically has been largely opportunistic and serendipitous.5,29
Indeed, the several successful examples of drug repurposing to date have not involved a precision therapeutic approach.30 Thus metformin, originally an antidiabetic drug, was serendipitously found to be effective in the treatment of various cancers, although the mechanisms for its antineoplastic activity still remain elusive.31–33
Undoubtedly the approach based on oncogene targets, due to its precision and flexibility, aids drug repurposing. However, the remarkable heterogeneity of neoplastic diseases poses an obstacle to such strategies.34–36
It may be more effective to use an understanding of the “the hallmarks of cancer” to mine “the new tricks of the old drug”, rather than blindly pursue similar targets thus missing out on the “metformin-like” success.
In this review, we will mainly focus on the anticancer activity of existing drugs that were not originally intended for cancer therapy to highlight the relevant signaling pathways and discuss the properties of these agents for the reasonable use of medication based on the hallmarks of cancer.
Those targeting sustaining proliferative signaling, resisting cell death, deregulating cellular energetics and avoiding immune destruction may be more effective in monotherapy, while those targeting evading growth suppressors, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genome instability and mutation and tumor-promoting inflammation may be more suitable for drug combination therapy.37,38
We also overview the various approaches that contribute to drug repurposing and discuss the major challenges encountered to date in drug repurposing. Overall, we hope that this article may help researchers and clinicians to get a deeper understanding of drug repurposing based on the ten hallmarks of cancer and help translate old drugs into accepted cancer guidelines.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331117/
More information: www.scientificamerican.com/art … cancer-much-earlier/
