Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Plain Language Summaries Improve Access to Medical Research

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Chris Winchester, DPhil
Chief Executive Officer, Oxford PharmaGenesis

Adeline Rosenberg, MSc
Senior Medical Writer, Oxford PharmaGenesis

Cancer Commons helps people make sense of the latest research on treatments for their distinct type of cancer. Meanwhile, a growing number of research papers now include a plain language summary (PLS)—an overview of the paper written for anybody to understand. Here, our Curious Dr. George discusses plain language summaries with Adeline Rosenberg, MSc, Senior Medical Writer at the healthcare communications company Oxford PharmaGenesis, and Chris Winchester, DPhil, Chief Executive Officer at Oxford PharmaGenesis.

Curious Dr. George: Patients and the public are very interested in the results of much clinical research. In the internet age, many medical articles intended for a research or physician audience are available open access. Yet, even structured abstracts may be difficult to understand. Some journals are now including plain language summaries (PLS) written by the authors. Can you tell us about this movement?

Adeline Rosenberg, MSc, and Chris Winchester, DPhil: Open-access publishing has been a pivotal step in the open-science movement, ensuring that peer-reviewed evidence of the highest quality is available to anyone who needs it, anywhere in the world. Research foundations and charities have taken the lead in funding transitions to open access, with pharmaceutical companies following in their wake.

The logical next step is to make sure that peer-reviewed evidence is understandable by all—this is an area in which pharmaceutical companies are leading the way. Article-associated plain language summaries (PLS) are elements of peer-reviewed journal articles written in jargon-free, accessible language for anyone to read—from patients, policymakers, and the public to non-specialist or time-poor researchers and clinicians. By communicating in a way that is understandable by all, PLS provide equity of information and a basis for shared decision making.

PLS are particularly important in cancer care, where the pace of scientific discovery and the expanding range of treatments can be overwhelming. PLS give clinicians, policymakers, patients, and caregivers the tools they need to empower patients and make decisions about patient care together.

As you can imagine, with a practice that’s still evolving, there is a variety of opinions on what works best. Some journals offer different formats of PLS, such as videos and infographics. Increasingly, journals are publishing short, text-based PLS, which can be indexed on directories such as PubMed alongside the abstract (such as in this cancer research paper). PLS need to be discoverable in order to be found and used, and indexing on PubMed is a great way of optimizing this.

Besides format, there are other PLS aspects on which a clear consensus is beginning to emerge. For example, many people involved in scientific publishing believe that PLS should be an integral part of each journal article and included in the peer-review process for reliability and credibility; that PLS development should involve the authors of the journal article for scientific accuracy and consistency with the overall message; and finally, that drafts of PLS should be user-tested with the target audience to help ensure that they are fit for their purpose and meet end-user needs.

Fortunately, many complementing projects are working towards developing consensus on best-practice guidelines. These include the Patient Focused Medicines Development initiative and the International Society for Medical Publication Professionals’ PLS Perspectives Working Group to name a few. Open Pharma (a collaboration facilitated by ourselves and colleagues at Oxford PharmaGenesis) contributed by publishing our recommendations, which were supported by a commentary on the value of standardizing publishing practices. One pharmaceutical company active in oncology, Ipsen, has even introduced a policy to include PLS in all journal articles reporting Ipsen-sponsored research involving human data. This represents a heartening commitment to transparency and trustworthiness.

As PLS grow in popularity, we hope to see more journals encouraging (or even requiring) the inclusion of PLS, more authors producing them, and more readers engaging with and advocating them. You can join the conversation on social media using #PlainLanguageSummaries—we look forward to hearing from you!

Rosenberg can be reached at and Dr. Winchester at

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Can Immunotherapy Be Effective for Brain Cancer?

Matt Warner, PhD
Scientist at Cancer Commons

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Immunotherapy has reshaped the cancer treatment landscape. This type of treatment boosts the immune system to fight cancer. However, for people with advanced brain cancer, immunotherapy options remain slim. Here, our Curious Dr. George asks Cancer Commons Scientist Matt Warner, PhD, about the challenges and future potential of immunotherapy for brain cancer.

Curious Dr. George: An accomplished molecular oncologist, you have now helped many brain cancer patients consider their options, both on your own and as part of virtual tumor boards. Immunotherapy has successfully revolutionized the treatment of many potentially lethal cancers. Why has the use of immunotherapy for brain malignancies seemed to lag?

Matt Warner, PhD: There are several reasons why cancers of the central nervous system (CNS) have been more challenging than other cancers to treat with immunotherapies. Despite recent studies demonstrating that the CNS is not as “immune privileged” as we once believed, it is still clear that 1) the unique anatomy of the brain and spinal cord, 2) the role of the blood-brain barrier at controlling which substances and immune cell subtypes can access the CNS, and 3) the limited presence of the lymphatic system within the CNS all decrease the ability of the immune system to patrol and attack cancers within the CNS versus other organs of the body.

Furthermore, CNS cancers often display fewer mutations in comparison to other cancers and therefore lack the immunogenicity to help the immune system identify and distinguish the cancer from the healthy neuronal tissue.

Lastly, as with all other cancers, you then have to compete with the immunosuppressive tumor microenvironment and the knowledge that chronic and excessive neuroinflammation as a result of hyperactivation of the immune system could also be detrimental to a patient. This presents concerns from a quality-of-life standpoint due to the impact of inflammation and swelling on the function of healthy neuronal tissue. It also poses disease management concerns because the immune system’s response to CNS cancer may also impact the survival, proliferation and invasiveness of gliomas.

CNS cancers therefore present some unique challenges for the immunotherapy-based treatments we currently have available in the clinic, highlighting why the clinical development of immunotherapies for these cancers has been less successful.

Despite these setbacks, I still believe immunotherapies will play a significant role in treating CNS cancers in the future. However, in order to be successful, this approach will most likely require novel combinations of immunotherapy-based treatments (for example, immune checkpoint inhibitors, dendritic cell and peptide-based anti-cancer vaccines, oncolytic viral therapies, and cellular therapy) with radiation, chemotherapies, targeted therapies, and/or Optune. Such combinations will no doubt help us move beyond the prior failings of immunotherapies being investigated as single agents, which lack the necessary activity to single-handedly enhance the immune system and treat cancers within the CNS.

Recent research findings provide some hope in this regard. For example, interim analyses from ongoing clinical studies and retrospective analyses from closed trials that investigated immune checkpoint inhibitors in glioma patients demonstrate that these drugs may need to be used around the time that patients are receiving their surgery, radiation therapy, or Optune treatment, and they may need to be targeted to patients with unique tumor mutational profiles. Additionally, more trials are now exploring combinations of immunotherapies and pharmacological agents to (hopefully) modulate the tumor microenvironment and make it more amenable to immunotherapy-based treatments.

Given how little we still understand about the brain and the activity of the immune system within the CNS, I am confident that we will one day celebrate the successes of immunotherapies in the treatment of CNS cancer patients.

Matt can be reached at

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Cancer Commons Adapts to Remain True to Our Mission

Shelley Frisbie
CFO & COO at Cancer Commons

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

People facing advanced cancer come to Cancer Commons to ensure they have all the information they need to make their best-possible cancer care decisions. Here, Curious Dr. George asks our CFO & COO Shelley Frisbie about recent updates to our organization.

Curious Dr. George: You have been the CFO of Cancer Commons for some time and recently added the COO title and duties to your position. How do you see Cancer Commons as a 501(c)(3) nonprofit organization as we seem to be emerging from the COVID-19 pandemic? I presume its core mission remains the same, but has the organization evolved, and do you anticipate additional changes?

Shelley Frisbie: There is no question that the pandemic profoundly affected nonprofits, because a significant percentage of philanthropic resources had to be redirected to the COVID-19 fight. Although things were lean at Cancer Commons, we learned from our clients what a tremendous need there is for compassionate, personalized support for those facing advanced cancer. The experience led us to commit even more deeply to our mission.

In support of this, we created the Director of Patient Services role and brought on a Patient Navigation Specialist. They serve as the crucial first points of contact, providing care to those who come to us feeling overwhelmed and uncertain. Together they guide clients through registration, assess needs and goals, and begin the process of identifying appropriate diagnostic and treatment options.

Thanks to an updated, more client-focused website—and the personal outreach done by our navigation team—we are seeing an increase in the number of registrations for Cancer Commons services. With philanthropy down, however, we have had to consider new ways of funding to meet the needs of those turning to us.

With this in mind, we launched several low-cost Enhanced Services, designed to provide a continuum of care:

  • Cancer Commons Plus, a subscription service that ensures registered patients stay connected with their Cancer Commons team for as long as needed;
  • Expanded Options & Navigation, to offer clients more detailed discussion and explanation of potential treatments, and assistance with obtaining molecular testing; and
  • Clinical Trials & Expanded Access Assistance, to address a need clients have been sharing for years.

Something that has not changed is Cancer Commons’ commitment to perpetual learning and open knowledge sharing to help current and future patients. We continue to work with our technology partner xCures on the XCELSIOR longitudinal study and are developing other collaborations to help us offer education and resources. Supported by a memorial sponsorship, we recently launched a series of quarterly webinars to provide critically needed information for cancer patients and caregivers—and introduce a whole new audience to our valuable services.

Everyone needs somewhere to turn when they hear those awful words “there’s nothing more to be done for your cancer.” The questions that arise seem endless. Patients and caregivers are looking for answers to be sure they have done everything possible. Cancer Commons helps provide those answers.

The organization has evolved and will continue to do so. In the near future, we will make Cancer Commons’ offerings even more interactive with the addition of chat service, and leverage partnerships with advocacy organizations and biotech companies so that we can offer new options as technology advances. Philanthropy will always be extremely important to sustain our free services, subsidize Enhanced Services for clients with demonstrated need, and to help us serve as many people as possible.

And as always, I invite anyone facing advanced cancer to sign up to receive one-on-one help from our compassionate experts. We are here for you.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Cellular Aging and the Development of Cancer

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Kaumudi Bhawe, PhD
Cancer Commons Scientist

Cancer is so often a disease of older people that a whole medical field, “oncogeriatrics,” exists to address the topic. Deeper understanding of the links between cancer and aging could lead to better treatments. Here, our Curious Dr. George asks Cancer Commons Clinical Scientist Kaumudi Bhawe, PhD, about the relationship between cancer and aging processes that occur in individual cells in our bodies—throughout our lives.

Curious Dr. George: As a molecular biologist, you have worked with many forms and elements of cancer cells. Are there any similarities between the processes of cellular aging and the development of cancer?

Dr. Bhawe: Cancer is a disease of aging. According to the National Cancer Institute (NCI), cancer incidence increases dramatically after age 50, with the median age of people diagnosed with cancer in the United States being 66. While chronological age is definitely a cause of cellular aging, it is not the only cause. In fact, the process of cellular aging is known to happen in cells right from the time a human embryo is still developing. What then, exactly, is cellular aging, and what does it have to do with cancer? This is a timely question with the recent publication of a paper in the scientific journal Cancer Discovery entitled “Hallmarks of Cancer: New Dimensions.” This article highlights aging—or “senescent”—cells as one of the newly acknowledged enabling characteristics of all cancers.

Aging cells can be defined by accumulated damage to the macromolecules, such as DNA and proteins, that are important for the cells to maintain themselves, to grow, and to divide. Certain molecules in a cell, are involved in a mechanism that surveys and repairs DNA damage each time the cell undergoes division. If there is more damage than can be repaired, an aging cell either dies or cannot divide, and goes into what is called irreversible cell-cycle arrest. The above-mentioned mechanism ensures that cells with faulty macromolecules are not increasing in number, and in this sense, it is a disease-preventing mechanism. For a very detailed overview of the DNA-damage-response mechanism and its relevance to cancer, you can read this scientific review article that was published last year.

However, once an aging cell enters irreversible cell-cycle arrest, it can stay alive for quite some time; up to months, as demonstrated by lab-based research. Not only can it stay alive, it can also evolve based on the cues it is receiving from its environment, and importantly, it can alter the very environment it finds itself in. It has been discovered that such senescent cells have an abnormal metabolism and secrete hundreds of different signaling molecules including proteins and lipids. Readers interested in learning more about this exciting field of study can start with this article from the scientific journal Communications Biology and this video from the news site Technology Networks.

Some of the ways in which cells can be induced to undergo aging/senescence include the slow natural aging caused by going through multiple cell-cycles, leading to telomere shortening, exposure to toxic chemicals (including chemotherapy) and radiation, exposure to reactive oxygen species (ROS), and activation of cancer-causing genes (oncogenes). So, you can see that as a cancerous tumor is forming, or even during treatment, senescence mechanisms are at work in at least some of the cancer cells as well as some of the non-cancerous surrounding (stromal) cells, such as fibroblasts, blood-vessel-forming cells, and immune cells.

Three key common features shared between aging cells and cancer-developing cells are:

1) accumulation of DNA defects

2) altered metabolic activity, and

3) an increase in secretion of environment-modulating molecules.

The current challenge lies in discovering and cataloging the specific details of each of these three features in order to identify true molecular similarities, differences, antagonism, and cooperation between the processes of aging and cancer. The NCI funds initiatives for cancer and aging research at premier institutes across the U.S. in the hopes of addressing this challenge and developing new, better strategies for cancer prevention and treatment.

Dr. Bhawe can be reached at

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

More Information from Less Tissue: Strata Oncology Excels

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Scott A. Tomlins, MD, PhD
Co-founder & Chief Medical Officer, Strata Oncology

Laura E. Lamb, PhD
Director of Translational Medicine, Strata Oncology


For a growing number of advanced cancer patients, molecular testing of tumor tissue is an essential step in identifying their best options for treatment. Strata Oncology is one company offering this kind of test. Here, our Curious Dr. George asks two of its leaders what sets Strata apart.

Curious Dr. George: No loop is stronger than its weakest link. In the “brain-to-brain” concept of laboratory testing for precision oncology, tumor specimen selection, collection, preservation, transportation, and processing are among the most important factors. What characteristics of your company’s approach to molecular diagnostics may be particularly advantageous for physicians to use to best guide cancer diagnosis and treatment?

Scott A. Tomlins, MD, PhD—Co-founder & Chief Medical Officer, Strata Oncology, and Laura E. Lamb, PhD—Director of Translational Medicine, Strata Oncology: Thank you for the opportunity to discuss this important topic. Strata Oncology’s mission is to accelerate the impact of precision medicine for patients with cancer by providing advanced molecular tests coupled to compelling clinical trials. To achieve this, we have carefully considered the brain-to-brain loop as it applies to clinical diagnostics. We are continuously innovating to ensure that all the steps involved in comprehensive molecular testing are optimized, standardized, and intelligently designed to improve benefit to the patient, while also working to reduce testing barriers to physicians and patients by partnering with healthcare systems and integrating Strata testing, education, and clinical trials system-wide.

All molecular testing at Strata is performed in a high-throughput, CAP-accredited and CLIA-certified laboratory, with numerous and redundant quality checks, controls, and standards in place. For example, all histology samples and molecular tests are reviewed and signed out by a single pathologist, which reduces variability, particularly for samples submitted as carcinoma of unknown primary. The latest clinical and molecular data is also reviewed by the lab director to ensure the most relevant information is used to guide downstream therapeutic decision-making. Our commercially-available test, StrataNGS®, has been clinically and analytically validated to assesses DNA and RNA in solid tumors. Importantly, as StrataNGS® sample requirements are some of the lowest in the industry (³2mm2), Strata has over a 99% success rate for patient samples passing all sample input requirements, resulting in over 60,000 tumor samples being tested.

StrataNGS® has been optimized for small tumor tissue samples and fills a critical unmet need. Unfortunately, as many as one out of every two patients with advanced cancer have insufficient tissue for other leading molecular tests. StrataNGS® requires 1/10th the tissue of other tests, which provides more patients the opportunity to benefit. By design, the StrataNGS® testing approach is modular: if the sample meets the overall sample requirements, the DNA, RNA, and tumor mutational burden are tested on three separate panels, which allows for the detected biomarkers to be reported from all or some of the panels, depending on whether the panel-specific quality control metrics had been met. Consequently, 94% of all samples tested by Strata will provide an informative result. Patients whose samples cannot be tested by Strata will not be charged for the test.

To simplify clinical reporting, StrataNGS®uses data-driven and clinical insights to provide an easy-to-follow report for confident clinical decision-making. The report summarizes matches to FDA-approved and guideline-recommended therapeutic regimens for all guideline-recommended genes, as well as matches to investigational therapies through clinical trials, including those available through Strata Oncology’s clinical trial partners, or the company’s own sponsored clinical trials Strata PATH and SENTINEL.

Strata Oncology builds processes within the company and through our partnerships with healthcare systems and biopharma companies to reduce testing hurdles for oncologists and their patients. In doing so, we aim to continue to bring the latest innovations in genomics, transcriptomics, and precision medicine to all patients with cancer, while collaborating with our partners to generate and test new biomarker-guided treatment hypotheses.

Dr. Tomlins can be reached at, and Dr. Lamb at

Meet Deb Christensen, Nurse Navigator for People Facing Advanced Cancer

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Deb Christensen, MSN, APRN, AOCNS, OCN
Director of Patient Services at Cancer Commons

For people with advanced cancer, making sense of the complexities of cancer treatment can be truly daunting. Enter the oncology nurse navigator (ONN), a nurse with specialized training to help patients overcome any barriers they may face in accessing high-quality cancer care. At Cancer Commons, our Director of Patient Services Deb Christensen, MSN, APRN, AOCNS, OCN, applies her ONN training to ensure that every patient receives the guidance they need. Here, our Curious Dr. George asks her about her work.

Curious Dr. George: You are in charge of patient services at Cancer Commons. How would you describe how you use your ONN skills every day to assist patients with advanced cancer who seek help at Cancer Commons?

Deb Christensen, MSN, APRN, AOCNS, OCN: My first real exposure to oncology was as a nurse navigator in a large healthcare organization. Care coordination is one of the main roles of the ONN. Networking and forming partnerships with other departments and physician offices was key to successfully helping people navigate the complex landscape of oncology care. I had the opportunity to participate on a committee of nurses who updated the Oncology Nursing Association Nurse Navigator Competencies in 2017 and was coeditor of Oncology Nurse Navigation: Delivering Patient-Centered Care Across the Continuum (second edition).

These experiences allowed me to share my passion for the role of the ONN and grow in the profession. After working as an ONN, and then serving as the system lead for the navigation program, I retired from the organization and joined Cancer Commons as a nurse navigator.

I am peoples’ first point of contact at Cancer Commons. I assist people through the registration process and then contact them to learn more about their cancer history and assess their needs, goals, and expectations. An essential ONN skill that I use consistently is the ability to communicate in a way people can understand and follow. Our patient navigation specialist, Lauren Levine, and I assist the patients and their families with retrieving medical records, collaborating with our Scientists, and checking in at key points in the cancer journey. Our goal is to make the entire process personalized and as simple as possible. The entire Cancer Commons team collaborates to help clients create a plan to discuss with their local oncology team. This action plan is complimentary, informed by the latest scientific research, and curated by PhD scientists.

My new role as Director of Patient Services evolved out of the Cancer Commons team’s desire to provide a more personalized experience to clients and offer new services. Our team helps clients understand their treatment options and take potential next steps. Additional services being implemented include a Cancer Commons Plus subscription for ongoing follow up and communication with the science team, clinical trial enrollment assistance, and other assistance offered by the hour. The ability to put clients first by providing non-biased treatment options and timely compassionate care is at the heart of everything we do at Cancer Commons.

Deb can be reached at

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Cardiometabolic Medications That Inhibit mTOR Might Help Prevent or Treat Cancer

Curious Dr. George Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column

William H. Bestermann Jr, MD Senior Clinical Advisor at Congruity Health

Many people believe that cancer is a metabolic disease. A biological process known as the mTOR pathway controls cellular metabolism by way of central signaling, and it is involved in tumor growth. Here, our Curious Dr. George asks William H. Bestermann Jr, MD, an internal medicine doctor, how medications that target the protein mTOR and its associated pathway could prevent or treat cancer. Dr. Bestermann is Senior Clinical Advisor at Congruity Health.

Curious Dr. George: What drugs that are currently approved for use by the U.S. Food and Drug Administration (FDA) inhibit mTOR and might be worthy of testing for potential off-label use for cancer prevention or therapy?

William H. Bestermann Jr, MD: A search including the terms mTOR and cancer in PubMed brings up 125,000 articles on the subject. Aberrant mTOR activation and signaling play a central role in many malignancies. Mutations that persistently activate mTOR are a basis of many familial cancer syndromes.

So, what is mTOR? It is an abbreviation for the mechanistic target of rapamycin, which is a natural compound produced by a fungus. Rapamycin is an antibiotic that is slowly released from the most modern heart artery stents to keep them from blocking with scar tissue and inflammation. It accomplishes that by inhibiting the protein mTOR, a master metabolic genetic switch. The mTOR pathway regulates many metabolic processes. In the fetus and child, it is essential to coordinate food availability with growth. Overeating, excess abdominal fat, and tobacco smoke cause increased oxidant production and growth factor signaling, which activate mTOR to increase arterial thicknessheart size, and the likelihood of cancer. mTOR has a reciprocal relationship with the protein AMPK, another genetic master metabolic switch. When mTOR is switched on, AMPK is switched off. mTOR and AMPK are a final common signaling pathway for genetic signaling that causes heart disease and malignancy. Medications that block oxidant production from that signaling or directly impact the mTOR/AMPK axis inhibit malignant transformation and tumor growth.

Several cardiometabolic medications decrease oxidant production and epidermal growth factor receptor (EGFR) activation to switch off mTOR and switch on AMPK. These include ACE inhibitors like lisinopril, ARBs like losartan, statins, and mineralocorticoid receptors (MR) like spironolactone. Smoking cessation has the same effect. Caloric restriction, intermittent fasting, rapamycin, exercise, and metformin directly inhibit mTOR and activate AMPK. SGLT2 inhibitors directly activate AMPK. These components of optimal medical therapy interfere with the core biology that causes cardiovascular disease and cancer. That is why they have a greater impact on major cardiovascular events and all-cause mortality than their impact on the target risk factor. These interventions don’t merely lower the target risk factor, they interfere with the molecular biology that causes cardiovascular diseases and cancer. They protect cells and organs.

Medications with a structure and function similar to rapamycin are called rapalogs. These are used to treat cancer and prevent organ transplant rejection, and they have potential in several additional conditions. The cardiometabolic medications listed in the previous paragraph do the same thing by directly or indirectly switching off mTOR and activating AMPK. Rapalogs inhibit both mTORC1 and mTORC2. The effect on mTORC1 is beneficial, and inhibiting mTORC2 may have harmful side effects. Like rapalogs, metformin has a beneficial effect in cancer prevention and treatment, which it produces by directly and specifically inhibiting mTORC1 and activating AMPK. Statins and ACE inhibitors are also associated with decreased cancer incidence. Similarly, high aldosterone levels have been associated with increased cancer risk, and eplerenone blocks those effects in a highly specific manner.

Research to further evaluate cardiometabolic medications for cancer prevention and treatment benefit should be a priority.

Dr. Bestermann can be reached at

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Using Virtual Trials to Screen for Potential Glioblastoma Therapies

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Al Musella, DPM
President, Musella Foundation For Brain Tumor Research & Information, Inc.

The existing drug development system “has failed miserably” for people with glioblastoma brain tumors, according to Al Musella, DPM, President of the Musella Foundation for Brain Tumor Research & Information, Inc. In partnership with Cancer Commons, his organization’s Brain Tumor Virtual Trial aims to speed discovery of promising new glioblastoma treatments.

Curious Dr. George: How might your Virtual Trial approach speed the process toward either validating or invalidating potential therapies for glioblastoma?

Al Musella, DPM: I have watched how the current drug development system works since 1992, and think we could do much better. There are many problems but the top ones, as they relate to malignant brain tumors, are:

  1. The current system is set up to try to find one magic bullet that will successfully treat the disease. This concept has worked reasonably well for some diseases, but for brain tumors it has failed miserably. I feel that the ultimate cure for brain tumors will be a combination approach, and under the current system, it is very difficult to get the individual components of that ultimate cocktail approved by the U.S. Food and Drug administration (FDA).
  2. There are not enough patients for the number of trials needed. About 10% of adult glioblastoma patients—about 2,000 per year—enter clinical trials. There are currently 318 glioblastoma trials open for enrollment, which means only six patients are available per trial per year. And some trials require large numbers; it takes years to accrue enough patients, and many trials never do.
  3. Phase 3 trials are too long and inflexible. In the last 25 years, only one phase 3 glioblastoma study showed a statistically significant improvement in survival, adding only 3 months to median survival. As patients are treated, we learn how to use the treatments better, but the rigid structure of a phase 3 trial doesn’t allow for modifications midstream. Rather than stop a trial, discard the results and start over, researchers complete a trial anyway, knowing that there may be a better way to use the drug.

I propose an alternative approach:

  1. All patients must be watched in a regulatory-grade registry so we learn from every patient—not just the 10% who may not even represent the typical patient.
  2. A formal randomized trial is perfect to prove that a combination works, but we are not yet at the point where we have a combination worthy of a full-scale phase 3 trial. So, if a patient desires entry into a formal trial, I propose they be given access to the registry to pick the most promising trials.
  3. We need a system in which experimental treatments get fast conditional approvals when they are shown to be relatively safe, with early evidence that they have the intended effect—even if that effect doesn’t result by itself in prolonged life. This allows us to use them in combinations and figure out how best to use them.
  4. Paying for medical drugs is a problem. The only way this can work is if patients do not have to pay high costs for their treatments, and if drug companies get paid for the treatments. This will allow access to the drug. The Virtual Trial system should keep drug costs down, as it will take the vast majority of time and money out of the drug development process and break the monopolies currently preventing many new drugs from being developed. In fact, I have proposed a bill (see below) that basically requires Medicare and Medicaid to pay for them and encourages private insurance to pay. We are working out the exact wording and are considering a “pay for performance” model, or a compromise in which costs for non-standard treatments cannot exceed what the standard of care would have cost.
  5. Doctors, or teams of researchers, can then think up the best combinations for each individual patient, and test them in small, fast, inexpensive (or free) virtual trials. They can see the ongoing results in all patients and quickly determine if a conditionally approved drug is worthy of continued usage—perhaps tweaking how it is given or the combinations used, or if it should be dropped. Once the ultimate cocktail is found, it can then be tested in a formal phase 3 trial.

I have been working on the components of this plan. We already have “right-to-try” laws passed in the U.S., but these did not work out as intended, mainly because of cost issues and fear that the FDA would hold usage of this pathway against a drug company. So, I am now working on a much-improved version of early access called the “Promising Pathway Act,” which was recently introduced into Congress. It fixed most of the problems with right-to-try laws and the FDA’s Accelerated Approval Program. It provides for conditional approval of treatments and requires all patients who use any conditionally approved drug to participate in a registry.

My organization, in partnership with Cancer Commons and its for-profit spinoff xCures, has set up a patient-navigation program that should be the model for how we approach all serious diseases. Our team of neuro-oncologists, PhD researchers, and nurse navigators—aided by an artificial intelligence engine—can look at our rapidly growing patient registry (we now have over 1,250 patients) and evaluate medical research, the rationales presented in tumor board meetings, and patients’ medical histories in order to come up with a list of treatment plan options that may be best for any given patient. The patient and their own doctor can select a treatment from our list, or they can elect to try whatever other treatments they want. Whatever they choose, our team then follows up on every patient to see the outcome of their chosen treatment. This way we learn from every patient.

We try to help patients get access to their chosen treatments, but the most promising options are usually impossible to access because the components are not yet approved, and either they are unavailable under expanded access or the drug companies won’t allow us to combine the experimental drugs.

Nonetheless, any doctor or researcher who is using a new combination of FDA-approved drugs for a patient can submit that treatment plan option to our system to be run as a virtual trial, allowing the doctor or researcher to quickly test the theory in their patient and use our system as a screening tool. They can try many combinations quickly, and if a particular combination shows a lot of promise, it can then be promoted to a traditional phase 3 trial to validate the findings.

Any treatment plan options validated in this way would be made up of FDA-approved treatments, so any doctor could prescribe them, allowing every brain tumor patient to have access—not just those perfect patients that fit into existing clinical trials.

In summary, our Virtual Trials could be used as a screening tool to figure out the best combinations, and how best to use treatments, which then can be tested in formal trials. Conversely, this approach could be used to quickly eliminate bad combinations. Having all results available in a central registry would help doctors from around the country avoid trying the same ineffective combinations.

Dr. Musella can be reached at

WATCH the 11th Annual Lundberg Institute Lecture: The COVID Labyrinth: Where Are We In It and How Do We Escape?

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Manage His Wife’s Metastatic Breast Cancer

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Richard B. Schwab, MD

Professor of Medicine – Division of Hematology/Oncology; Medical Director, Koman Family Outpatient Pavilion Infusion Center – UC San Diego Moores Cancer Center

For most people with breast cancer, a lump is the first sign that leads to diagnosis. But some cases are not detected until after spread has already occurred. Here, our Curious Dr. George asks Richard B. Schwab, MD, how he would approach such a case if his own wife were the patient. Dr. Schwab is Professor of Medicine in the Division of Hematology/Oncology and Medical Director of the Koman Family Outpatient Pavilion Infusion Center at U.C. San Diego Moores Cancer Center.

Curious Dr. George: How would you, as a breast cancer expert, manage your wife’s cancer if it were to present as shortness of breath or back pain, with a breast mass only then detected?

Richard B. Schwab, MD: Doctors frequently take care of their family members for minor problems; cancer is not one of them. Even caring for patients, managing one’s own anxiety about the normal uncertainties of medicine is not easy. Managing of my wife’s cancer would not be possible, so I would have one of my excellent colleagues be her oncologist.

That said, I would be answering my wife’s questions about this frightening situation and trying to guide her. She gets her screening mammogram every year, so presenting with metastatic breast cancer would be very unusual. Only 5% of breast cancer is de novo metastatic, and many of these patients did not have recommended screening before diagnosis. However, screening mammograms are not perfect, so your hypothetical scenario is possible.

If she was short of breath, I think we would utilize the emergency department. Although cancer is usually a relatively slow process, there are rare times when patients can become very ill during the normal time required for diagnosis and treatment initiation. CT scans can be done quickly and could identify a pulmonary embolism, pleural effusion, or lymphangitic spread. Starting appropriate therapy quickly (anti-coagulation, thoracentesis, or chemotherapy respectively) could be critically important.

Making a pathologic diagnosis would be the next step, and would radically alter treatment (and life) plans. Breast cancer is not one disease. Oddly we would be hoping for an aggressive estrogen receptor-negative and HER2-positive cancer. These cancers are highly responsive to numerous treatments, and cures—even with metastatic disease—are becoming more and more common. A triple-negative cancer would be complicated. Some patients with triple-negative breast cancer, particularly limited to the lungs, do end up cured, but these cases are rare and overall this type of breast cancer has the fewest treatment options. Last but most common, particularly if her cancer had spread to the bones, would be estrogen receptor-positive disease. These cancers generally grow more slowly and on average patients survive longer with this type of disease. However, these cancers are never truly cured, although for older patients lifelong disease control can sometimes be obtained. For a patient as young as my wife new therapies would be needed to have any reasonable hope of lifelong disease control.

Which location to biopsy is a common challenge we would need to address. Biopsy of the breast is the easiest, but may not reflect the more dangerous disease that has spread to other organs. Lung biopsy has some additional risk, it is anxiety provoking, and sample quantity (or even successful sampling) can be challenging. Biopsy of the bone, while very safe, can give unreliable results due to the need to decalcify the sample prior to testing. The details of the patient’s case and the expertise of the doctor performing the biopsy matter. Having expert trusted colleagues in radiology and pulmonology would be a significant advantage for my wife.

I mentioned the idea of truly curing my wife. I define true cure as a lack of cancer progression for at least 5 years after stopping therapy. I have cared for many patients with metastatic disease that has been cured, and that knowledge would help my family get through what is fortunately only a hypothetical situation.

Dr. Schwab can be reached at