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

Using Artificial Intelligence to Match Combination Targeted Therapies in Oncology

A Q&A with Razelle Kurzrock, MD, Director of the Center for Personalized Cancer Therapy and the Rare Tumor Clinic at U.C. San Diego, and Co-Founder and Board Member of CureMatch, Inc. Email: razelle@curematch.com

Q: The new understanding of many cancers brought about by molecular testing has led to a whole new field: precision oncology, which emphasizes targeted and immunotherapy. While promising, and sometimes spectacularly successful, targeted monotherapy has limitations. The evolution of targeted and immunotherapy by combinations of drugs offers new scientific options for cancer patients. But there are so many new molecular findings, so many new investigational drugs or drugs newly approved by the U.S. Food and Drug Administration (FDA), and so few appropriate patients, that matching patients to best drug combinations can be a mathematical nightmare. What have you and your company CureMatch to offer to help with this dilemma?

A: Thank you for this excellent question. As you correctly noted, tumors, even those that share the same histologic origin, are highly heterogenous and unique at the molecular level. Therefore, the existing paradigm of treating all cancer patients based on their tumor’s tissue of origin, even by adding minimal biomarker stratification criteria, has proven largely inadequate. The advent of molecular diagnostics allows for improved patient stratification during therapy selection; however, most patients are still treated with monotherapies, which ultimately perform poorly.

Early data show that individualized matched combination therapies targeting most of a patient’s druggable aberrations are associated with improved outcome. However, selecting the “right” combination in routine oncology practice could be challenging. The average oncologist is pressed for time, seeing approximately 350 new patients annually and up to 100 patients per week. To complicate matters, even if an oncologist wanted to rationally combine only the approximately 300 FDA-approved “oncology-specific” drugs, there would be estimated 45,000 possible two-drug and approximately 4.5M three-drug combinations. Even molecular tumor boards found in some academic centers rely largely upon expert knowledge and experience to tailor personalized combination treatment strategies for hundreds of patients with unique molecular profiles. Clearly, the drug selection process is rapidly outpacing human capabilities, and software tools are needed to help with data analytics.

Bionov™, a rule-based artificial intelligence platform developed by CureMatch, utilizes the latest data available on targeted, immuno-oncology, hormone therapy, and cytotoxic agents. Bionov™ employs an algorithm that matches patients with monotherapy and multidrug regimens based on their available tumor “omic” profile. Drug regimens provided in the Bionov™ report are ranked using a predictive “Bionov™ score” that reflects the degree to which a given regimen matches the patient’s molecular profile.

To generate our database, we curated all FDA-approved drugs relevant to oncology for their biological impact on their targets. Recently, we added oncology drugs that have been approved by the European Medicines Agency (EMA) to our database, and FDA/EMA-approved drugs are kept up-to-date based on their respective labeling changes. Further, we researched and curated preclinical and clinical literature pertaining to the efficacy of these drugs, including drug toxicities and contraindications. The CureMatch scientific team conducts literature reviews on a routine basis to ensure drug efficacy is kept current.

Our methodology has been validated in several studies, and I will highlight two of them here. First, in a retrospective meta-analysis of 70 exceptional responders for whom molecular profiling data was available, Bionov™ correctly ranked the response to all treatment regimens (including failed regimens) with 84% sensitivity and 77% specificity. This analysis demonstrates how the Bionov™ algorithm is able to discriminate, solely on the basis of the molecular fingerprints of a patient’s cancer, treatment regimens that favor a positive outcome from those that are more likely to be associated with an unsuccessful response. The second study I want to highlight is a prospective clinical trial: our group found that a higher matching score (similar to the Bionov™ score) was an independent predictor of increased disease control rate, prolonged progression-free (PFS), and overall survival rates. Furthermore, PFS was significantly improved in 75% of patients treated with combination therapies based on high matching scores.

We live in the “big data” generation. As the patient progresses through their treatment journey, massive amounts of actionable molecular information are generated, and clinical oncologists may not be entirely prepared to effectively utilize it. We believe that predictive analytics models—such as Bionov™—can provide an alternative framework for modern clinical practice, collaborating with and empowering oncologists in their decision-making process.

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

Comprehensive Molecular Testing Needed for Stage IV Lung Cancer

A Q&A with David Spigel, MD, Chief Scientific Officer, Director of the Lung Cancer Research Program, and Principal Investigator at Sarah Cannon Research Institute. Email: dspigel@tnonc.com

Q: You are an expert medical oncologist with particular interest in lung cancer. The various forms of lung cancer are serious diagnoses, all potentially lethal malignancies. There are theoretical, investigational, and clinical justifications to perform molecular testing of these tumors. In your opinion, should such testing target specific mutations, panels of genes, or use next-generation sequencing (NGS) for whole-exome or genome analysis? At what point in a patient’s disease should molecular testing be performed?

A: Caring for patients with lung cancer today requires broad NGS at diagnosis for stage IV disease. There are multiple potential targets, and spot testing for individual mutations is simply inefficient in my view. We need to test for mutations in EGFR, ROS, ALK, MET, and BRAF—and also TRK and PD-L1. HER2 is nearing similar importance, and others are not far behind. I need to know about mutations in these genes as soon as possible to make treatment decisions, not the least of which is deciding whether a patient will qualify for a clinical trial.

Q: What challenges do you and other oncologists face in getting the molecular tests you need?

A: It’s a bit ridiculous that we have local and “send out” testing, and each can be imperfect if the labs are not using NGS. Currently, blood has become the easiest for me to get the day I meet a patient, and it takes five to eight days for results. It gets the ball rolling so to speak. I have tissue tested by commercial vendors, but those results can take three to four weeks—and that’s simply too long to make treatment decisions for a lot of folks (and me).

In the future, we will need a one-stop shop that offers the best-in-class technology in the shortest amount of time with the least amount of material. I bet that will be blood. And lung cancer is just the first malignancy that makes the strongest case for broad upfront testing; there’s no reason this won’t be also true for every cancer we treat one day.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Weathering the Perfect Storm of the Vaping Threat

A Q&A with Alan Blum, MD, who founded the Center for the Study of Tobacco and Society in 1999 at The University of Alabama, where he serves as Professor and Gerald Leon Wallace, MD, Endowed Chair in Family Medicine. Email: ablum@ua.edu

Q: Inhalation of carcinogens and other harmful chemicals in tobacco smoke is responsible for more American deaths—especially from cancer—than any other one factor. Nicotine addiction is central to that pathologic process. The relatively recent invention of the e-cigarette seemed to offer great hope as an alternative nicotine-delivery device that most likely did not cause cancer, and could prevent nicotine addicts from having to smoke. Yet, the “unintended” consequence of masses of new young nicotine addicts produced by unregulated for-profit vaping companies has created a new public health disaster. How might the U.S. Congress and the U.S. Food and Drug Administration (FDA) have better managed this threat?

A: In 2009, Congress passed a bill giving the FDA the authority to regulate tobacco products. When the treacly named Family Smoking Prevention and Tobacco Control Act was signed by President Obama, the bill’s proponents—notably, the Washington lobbying group Campaign for Tobacco-Free Kids—touted it as a long-awaited defeat for Big Tobacco. When it was revealed that the Campaign had secretly co-written the bill with Altria, maker of the top-selling cigarette Marlboro, we realized that the brand’s iconic cowboy wouldn’t be riding off into the sunset just yet.

But few could have predicted that the efforts to protect Americans from the harmfulness of tobacco would become more confused and convoluted by adding it to the FDA’s portfolio.

Because the FDA is the nation’s watchdog over medications and medical devices, a provision in the 2009 bill distinguishes drugs and devices from tobacco products, in order to prevent duplicative regulation by different centers within the FDA. And therein lies the origin of the unfettered explosion of vaping—the inhaling of a heated, flavored nicotine solution from an e-cigarette or other device: in their eagerness to get the FDA bill passed, Senate Democrats rejected a Republican amendment to regulate e-cigarettes as tobacco products and deliberately left them out of the bill. After all, proponents reasoned, e-cigarettes were new and expensive, and they were manufactured by just a handful of companies. The proponents also counted on using a provision of the bill in which the FDA could “deem” as tobacco products both e-cigarettes as well as future nicotine-containing products that regulators couldn’t yet envision.

But a not-so-funny thing happened. While the FDA hemmed and hawed about these new-fangled electronic nicotine delivery systems (now called ENDS), hundreds of manufacturers entered the market, costs dramatically dropped, and e-cigarettes could be purchased at any convenience store for the price of a pack of Marlboros.

Finally, in 2016, the FDA issued its deeming rule that included e-cigarettes as tobacco products subject to the agency’s regulatory authority. In July 2019, a U.S. District Court in Maryland upheld the FDA’s rule. Meanwhile, products such as the Juul e-cigarette, craftily designed to resemble a USB drive and promoted through social media to the wired generation, became an essential accoutrement of high school and college students. That Juul was also engineered to deliver nicotine more rapidly than any previous e-cigarette—and came in appealing flavors such as mango and mint—contributed to its capturing 75% of the e-cigarette market just three years after it was introduced in 2014.

In December 2018, Altria paid $12.8 billion for a 35% stake in Juul Labs, Inc. At the same time, the vape shop industry burgeoned, as did online sellers of e-liquids and paraphernalia aimed at a counter-culture that rejected commercial products. The legalization and commercialization of marijuana by several states also led to the proliferation of e-cannabis with THC-containing e-liquids. This in turn has resulted in an outbreak of vaping-related pulmonary illness in 2019, causing more than 40 deaths and sickening more than 2100 users of electronic vaping devices.

Thus, the FDA lost a full decade in which it could have required manufacturer registration and ingredient-reporting, inspected e-liquid-making facilities, and acted against adulterated or misbranded products. Lost, too, was the opportunity to slow the introduction of e-cigarettes, to temper so-called harm reduction health claims about these products compared to cigarettes, to verify their value in smoking cessation, and to thwart their marketing to young people.

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

Using Molecular Testing to Guide Treatment for Advanced Colorectal Cancer

A Q&A with Kalpana Kannan, PhD, former Scientist at Cancer Commons

Q: Colorectal cancer is common, and although many cases in earlier stages are cured by surgery alone or with adjuvant chemotherapy, it is still a lethal threat for many patients. Nonetheless, several new targeted and immunotherapeutic agents are now available. When should patients receive molecular testing for their colorectal cancer, what information should especially be sought, and which therapeutic agents are likely to be effective?

A: For every patient who is diagnosed with stage IV colorectal cancer (mCRC), complete molecular profiling of their tumor is highly recommended. It is important for patients to know their microsatellite status, RAS (KRAS and NRAS) and BRAF mutations, and HER2 amplification status at a minimum. Depending on these molecular profiling results, targeted therapy or immunotherapy may be applicable.

Microsatellite status refers to the status of short tandem repeats of DNA that are present throughout the human genome. Since microsatellites have a repetitive sequence, they are prone to mutations. These mutations are usually corrected by the DNA mismatch repair (dMMR) system. Tumors with a defective dMMR system that cannot adequately repair the mutations have microsatellites of different lengths than would be found in the germline DNA. This molecular phenotype is called microsatellite instability (MSI). Tumors are generally categorized as MSI-high (MSI-H), MSI-low, or microsatellite stable (MSS).

MSI-H or dMMR tumors are very sensitive to immune checkpoint blockade. The U.S. Food and Drug Administration has approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of patients with MSI-H/dMMR mCRC following progression with chemotherapy. Recently, the immunotherapy combination of nivolumab and ipilimumab showed an overall response rate of 60% in the front-line setting (before any chemotherapy) in a clinical trial with 45 patients. So, immunotherapy has an important role in the treatment of this population of patients who seem to not benefit as much with conventional chemotherapy.

For most other patients, in fact 95% of mCRC patients whose tumors are MSS or MMR-proficient, single-agent immune checkpoint inhibitors are not advisable. Combination treatments of checkpoint inhibitors with kinase inhibitors (such as regorafenib) and VEGF-targeting agents (bevacizumab) are currently being evaluated in clinical trials and are showing some promising results. In a phase 1b trial of the combination of regorafenib and nivolumab, an overall response rate of 33% was observed in patients with MSS tumors. While this is promising, it is important to focus on targeting the other alterations that may be present in these patients’ tumors.

Most often, these are KRAS mutations, which are present in about 30–50% of CRCs. The most frequent mutations in the KRAS gene are in codons 12 and 13, namely, KRAS G12V, G12C, G13D, and others. Mutations at these positions result in the activation of RAS. Considered to be undruggable for a long time, only recently have efforts to target KRAS paid off. AMG 510 is an oral inhibitor of KRAS G12C. Clinical trial results with this agent in CRC indicate a disease control rate of 92% (1 partial response and 10 stable disease among 29 patients).

Various other strategies to target RAS mutations are currently in trials. These include targeting of EGFR; targeting of the downstream effectors RAF, MEK, and ERK; and targeting of synthetic lethal interactions with CDK4, SHP2, and PLK1.

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Emphasizing Oncogeriatrics

A Q&A with Nicolò Matteo Luca Battisti, MD, Medical Oncologist at The Royal Marsden NHS Foundation Trust, London, United Kingdom, and Chair of the Young Interest Group of the International Society of Geriatric Oncology (SIOG); nicolo.battisti@gmail.com

Q: Everyone knows that the practice of pediatric oncology is very different from adult oncology. How does the growing field of oncogeriatrics differ from usual adult oncology?

A: In my opinion geriatric oncology is a large part of the routine oncology practice, and every oncologist is a geriatric oncologist. Cancer is a disease of older adults, and currently, approximately 50 percent of all cases and 70 percent of related deaths occur in adults aged 65 or older. In the context of ongoing demographic changes, with average life expectancy increasing worldwide, the incidence of cancer in older adults is obviously expected to increase.

Moreover, older adults have always been underrepresented in clinical trials investigating the management of cancer and which have defined the current standard of care. Older patients are more frequently excluded due to strict inclusion and exclusion criteria that are very difficult for them to match, logistical barriers that sometimes make enrollment quite challenging for this age group, and concerns and misconceptions of treating physicians. This limits the external validity of the evidence base that currently guides management of cancer in older patients.

Older adults are a very heterogeneous patient population due to a number of challenges unique to this age group. First, we observe a gradual decline in function and reserve of organs—including the liver, the kidneys, bone marrow, the heart, and muscle—which may affect the pharmacokinetics of drugs and increase the risk of complications for systemic and local anticancer treatments. Second, an increased burden of comorbidities may affect the life expectancy of these patients and again affect treatment outcomes. In this age group, polypharmacy is a common issue that makes patients particularly prone to the risk of drug interactions. Functional impairment is also prevalent in this cohort and may increase the risk of adverse events independently of other factors, including comorbidities. Older adults also tend to value quality of life over “quantity of life,” which may make decision-making in this age group even more complicated. Further issues may also involve psychological and social aspects, financial toxicity, and the presence and role of caregivers.

All these factors make the management of cancer in older adults particularly challenging, as oncologists are not able to simply apply guidelines and consensus in this age group. A comprehensive geriatric assessment should always guide decision-making in this population.

On the other hand, this increased complexity makes the field particularly rewarding, since these challenges provide oncologists a unique opportunity to aim for a truly personalised approach. This does not necessarily involve only new biomarkers and fancy new systemic treatments, but also a more holistic approach which should take into consideration all the aspects that I briefly mentioned here in order to recommend the most appropriate treatment plan in the context of life expectancy and our patients’ preferences.

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

Fixed and Variable Factors that Impact a Brain Tumor Patient’s Prognosis

A Q&A with Burt Nabors, MD, Professor and Director of the Division of Neuro-oncology at the University of Alabama, Birmingham, and a member of the Cancer Commons Brain Tumor Advisory Board; bnabors@uabmc.edu

Q: Primary brain gliomas can be devastating, often deadly, malignancies. Obvious prognostic factors include whether they are grade 1, 2, 3, or 4; their extent of growth prior to diagnosis (stage); and their location, such as in the brain stem. What are other key factors that affect prognosis? Some say that the skill of the original surgeon is the most important prognostic factor. Others suggest that the size (case volume) of the initial treating institution is most important. What do you think?

A: An excellent question and one I may try to answer in two ways. The first are the known and well-quantified prognostic factors. The two most powerful are the patient’s age and their performance status. Age is a pretty clear factor and one we cannot alter. We in the neuro-oncology community are seeing increased attention to treatment recommendations based on age, both at the young and older ends of the spectrum. These efforts do appear to provide brain tumor patients in those spaces improved outcomes. However, as a modifiable prognostic factor, age is not one.

A patient’s performance status is, at the core, a measure of how well they retain their station in life and can manage their activities of daily living independently. It most likely reflects the summation of several other factors, such as the location of the tumor, the grade, and the ability of the neurosurgeon to safely resect (remove) tumor. When looking simply at tumor location, we do see improved outcomes for tumors in the non-dominant hemisphere or in more silent regions, such as the frontal or anterior temporal lobes compared to more eloquent or vulnerable brain regions. However, again, the location of the tumor is not modifiable by the individual patient. It is where it is.

As you suggest, another—and modifiable—way to consider this question is to focus on the experience and skill of the neurosurgeon. I would submit the factors that have the greatest impact here are the training environment for the neurosurgeon, the experience and interest of the neurosurgeon in brain cancer, and the volume of the treatment facility. Surgery at centers involved in high volumes of brain tumor surgery with neurosurgeons who are dedicated to advancing the practice of surgical intervention is an important consideration.

The current practice of the neurosurgeon also has a significant impact on patient outcomes. This has been well quantified and published, clearly for high-grade glial tumors such as glioblastoma, but also for lower-grade tumors such as astrocytoma and oligodendroglioma WHO II. This need for a dedicated practice is typically seen in environments that offer pre-operative neurological function mapping, advanced imaging modalities, and intraoperative awake craniotomy with cortical mapping. When this degree of neurosurgical sophistication is available, it is often in settings with multidisciplinary groups, including a research base with an intense interest and focus on brain cancers.

An unfortunate current reality is that, most often, settings with this degree of sophistication are in our larger urban centers, where ease of access for patients living and presenting in a more rural environment can be quite a challenge. Creating opportunities to provide access and equal care to all remains a significant part of the neuro-oncology mission and challenge.

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

How to Treat Uveal Melanoma that Recurs in the Liver?

A Q&A with Emma Shtivelman, PhD, Chief Scientist at Cancer Commons; emma@cancercommons.org

Q: Malignant melanoma may arise from multiple sites, including the eye.

What would you recommend be done for a 50-year-old man in the San Francisco Bay Area who was entirely well for nine years after undergoing enucleation surgery for a large uveal melanoma, but has now been informed by his physician that he may have a mass in his liver?

A: Uveal melanoma (UM), sometimes called ocular melanoma, is a rare type of cancer, and there are no definitive guidelines for its treatment once it spreads to other organs. Because of the location of the tumor and interference with vision, most patients are diagnosed when there are no metastases. However, many patients (up to 50%) who have successful surgery and/or radiation for the primary tumor will develop metastases, which occur most often (in almost 90% of cases) in the liver.

The mutational landscape of UM is well described, but this has not translated into effective targeted treatments, in spite of clinical research efforts that have tested potentially relevant drugs. The treatment options for metastatic UM (mUM) are not many, and none are endorsed by clinical guidelines nor approved by the U.S. Food and Drug Administration (FDA), underscoring the lack of progress in treatment of mUM.

For the patient with late recurrence of UM described in your question, my first recommendation would be to seek a clinical trial. The main reasons for this are:

  1. No chemotherapy regimen is effective in mUM.
  2. While the treatment landscape of cutaneous melanoma was transformed by the introduction of BRAF/MEK-targeting drugs and by immune checkpoint blockade (ICB), this transformation has not extended to UM. BRAF mutations are practically non-existent in UM, and so far, responses to ICB have been less than spectacular. Only a low percentage of patients respond to monotherapy with anti-PD-1 or anti-CTLA4 drugs.
  3. The combination of nivolumab and ipilimumab reported an overall response rate of 16% and disease stabilization in 47%. There is an obvious need to improve the response rate, not to mention the fact that this combination is not FDA-approved for mUM, and may not be available to some mUM patients.

Liver-directed treatments present a currently available option for liver-dominant disease, and are available in a number of larger cancer clinics. They usually involve liver embolization (chemo, radio, immune) or percutaneous hepatic infusion. Precision radiation—and, less frequently, radiofrequency or cryoablation—and surgery can be used as well. Liver-directed treatments translate most often into prolongation of progression-free survival (PFS), sometimes offering a significant survival benefit. Systemic treatment (for now, most likely dual ICB) should be considered alongside or after liver-directed interventions. Recent reports based on treatment of a small number of patients indicate better PFS and overall survival (OS) in patients who received liver radioembolization with Yittrium-90 and ICB, or chemoembolization and ICB.

So, my advice to the 50-year-old patient with mUM would be, first, to biopsy the liver tumor to confirm the diagnosis and to perform mutational testing. Mutational testing can test for possible predictors of the patient’s response to combined ICB and for the slim possibility that a targetable mutation is present.

For liver-dominant disease, liver embolization should be considered as the first line of treatment, and/or enrollment in one of several ongoing clinical trials.

The current clinical trial landscape includes:

  1. ICB combined with liver embolization (Y90 SIR-Spheres or immunoembolization)
  2. Tebentafusp(IMCgp100), a bispecific antibody bridging CD3 on T cells and gp100 on melanoma cells. Tebentafusp has received the FDA fact-track designation for uveal melanoma, based on the results of a small clinical trial in which OS at 1 year was 74%. It is available in one trial only, and that trial is unfortunately randomized to investigator’s choice of dacarbazine or a single immune checkpoint drug. Moreover, it is only relevant to patients who have a certain HLA type: HLA-A*0201 (found in 44% of the population in general).
  3. A virus-based drug: oncolytic VSV-IFNbetaTYRP1 (vesicular stomatitis virus expressing IFNbeta and tyrosinase), which is designed to replicate in and induce cytolysis of cancer cells specifically, and instigate an immune response.
  4. If a BAP1 mutation is present (and most often it is in mUM), it is possible that treatment with a PARP inhibitor will have a desired effect.
  5. Cell-based treatments. These include a CAR T-cell approach with T cells modified to target the protein SLC45A2, which is often present on uveal melanoma, and tumor-infiltrating lymphocytes (TILs).

The last three trial options are new, and have not reported even preliminary results. Liver embolization (if not offered in the trial) could be considered first to reduce the tumor burden and thus hopefully increase the possible efficacy of investigational approaches.

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

The Importance of Brain Tumor-Initiating Cells in Glioblastoma

A Q&A with Anita Hjelmeland, PhD, Associate Professor of Cell, Developmental and Integrative Biology at the University of Alabama Birmingham School of Medicine

Q: The inner workings of malignant gliomas are mysterious to many of us. Why does the prognosis of patients with these tumors remain poor?

A: Glioblastoma is a primary brain tumor that is treated with surgery, radiation, and chemotherapy. While surgical removal of glioblastoma is a goal, glioblastoma cells move into the normal brain where they cannot be removed and where many chemical therapies do not reach. The latter is due to a special wall of blood vessels called the blood-brain barrier that protects the brain from toxins. To overcome these obstacles, researchers are developing ways to identify tumor cells during surgery and break down the blood brain barrier for short periods of time.

Another reason that glioblastoma is difficult to treat involves the body’s defense against invaders—the immune system. The immune system usually will not attack cells it recognizes as “self” (if it does, autoimmune diseases will develop), but special immune cells can recognize and destroy infected self cells that have different proteins on the cell surface than do normal cells. Glioblastoma cells also have different-from-normal proteins that could be targeted by drugs, but glioblastoma cells often block the activity of immune cells. To improve the treatment of glioblastoma, there are clinical trials testing the effects of drugs or viruses that are designed to activate the immune system.

A final reason that glioblastoma cures remain elusive is that tumor cells are not all the same. There are different genetic or mutational features that could lead to resistance to any one targeted therapy. Glioblastoma cells also behave differently depending on their environment: for example, lower oxygen levels can promote resistance to radiation. Furthermore, glioblastoma cells can resemble specialized cells in the brain to differing degrees, reflecting a difference in stem-cell state. To improve our ability to target all tumor cells, researchers seek to identify ways to prevent therapeutic resistance and combine therapies to try to make them more effective.

Q: Your research delves seriously into the role of brain tumor-initiating cells (BTICs). What are BTICs, what do they do, and how might an understanding of them lead to improved therapies? 

A: Glioblastoma cells can look and act more or less like normal stem cells in the brain, the neural stem cells. Neural stem cells are important during development and in brain diseases because they remake themselves, a process called self-renewal, and make specialized (differentiated) brain cells like neurons. Neural stem cells and differentiated brain cells can be distinguished by levels of different proteins called markers, which can also be expressed by glioblastoma cells. Glioblastoma cells with neural stem cell markers and the ability to self-renew or differentiate are called cancer stem cells or glioblastoma stem cells. Human glioblastoma stem cells have a greater capacity to cause tumors to initiate or grow in mice without an immune system: this tumor-initiating ability has led to the alternative name of BTICs.

BTICs can comprise only a small portion of the overall number of tumor cells present but could be especially important to eradicate. BTICs better survive chemo- and radiotherapy, and can live in environments where therapies are less effective. BTICs possess a high capacity to invade and readily move into the normal brain. Therefore, BTICs are believed to be the cells that remain after surgery, radiation or chemotherapy. Any such cells that remain after treatment, as their name denotes, can stimulate glioblastoma to grow anew. Thus, it is imperative that we make strong efforts to understand how to eradicate BTICs along with the more differentiated tumor cells in the hope of extending patient survival. Our ability to ever cure glioblastoma could rest upon that success.

It is important to note that glioblastoma is not alone in harboring tumor-initiating cells. By studying ways to combat BTICs in glioblastoma, progress is likely to be made towards understanding better therapies for other malignancies with such a capacity for therapeutic resistance and recurrence.

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

Navigating Pancreatic Cancer—The Basics

A Q&A with Lola Rahib, PhD, Lead Scientist, Pancreas Cancer, at Cancer Commons, Los Altos, CA

Q: Navigating a pancreatic cancer diagnosis can be overwhelming and confusing for patients and their loved ones. How can patients and their caregivers ensure having the knowledge, support, and plan they need to be able to navigate treatment options and other aspects of the disease?

A: Patients and caregivers can regain control of a chaotic and anxiety-inducing process by making sure they maintain and organize detailed medical records and information about diagnosis, treatments, and options. As a patient it is critical to advocate for yourself and your needs. If this is not possible, ensure a designated family member or caretaker can advocate on your behalf.

Q: What are the specific aspects of the disease that are most important to navigate?

A: A little over ten years ago, Dr. Brown began a series of preclinical studies to test the possibility that an important contributor to the recurrence of malignant brain tumors after radiation therapy was reconstitution of the tumor vasculature. Specifically, he hypothesized that this reconstitution stemmed at least in part from circulating pro-angiogenic cells not in the tumor at the time of radiation—a phenomenon known as “vasculogenesis.” In agreement with this concept, a finding common to all of the tumor models he tested was a major influx into the irradiated tumors of bone marrow-derived cells, most of which were macrophages, that correlated with when tumors began to grow two to three weeks after completion of radiation. Further, he demonstrated that the mechanism for this influx was a radiation-induced hypoxia that triggered a cascade that led to the secretion of stromal cell-derived factor-1 (SDF-1), which was instrumental in attracting these cells. The apparent importance of excluding these cells’ entry into tumors post-irradiation suggests a new treatment strategy, which we call macrophage exclusion radiation therapy (MERT).

In August of 2014, based on these strong preclinical data, we launched a phase I/II clinical trial of MERT. This study examined the effects of administering a four-week continuous infusion of plerixafor (Mozibil)—the only commercially available agent that blocked the SDF-1 binding receptor CXCR4—at the end of irradiation to newly diagnosed GBM patients (NCT01977677). We enrolled 29 patients and established in phase 1 that the treatment was well tolerated at a dose that resulted in plerixafor serum values being maintained above the threshold level for CXCR4 blockade.

Two findings in phase II of this trial were particularly noteworthy: (i) a persistently lower relative cerebral blood volume within the irradiated field, and (ii) a much-improved control of the cancer in the treated field.

The noted overall median survival of nearly 22 months compared favorably with the best results obtained in other studies of GBM. However, it fell short of the dramatic improvements in survival noted in our preclinical studies, which utilized whole-brain irradiation (WBRT). WBRT was abandoned by clinicians in the early 1990s as a treatment for GBM because the high rate of local recurrence did not seem to justify the associated potential treatment-related issues of irradiating the entire brain (i.e., cognitive decline). However, we have shown that MERT is actually radioprotective for cognitive decline in rats given WBRT, consistent with the fact that tissue inflammation after radiation is related in large part to macrophage entry. Therefore, we have opened a new trial (currently open to accrual)using the same basic strategy in which a modest dose of WBRT has been added. Our expectation is that the widened radiation fields will further patient survival without excessive toxicity.

It is also important to note that the MERT strategy can be applied to any solid tumor in which local control using radiation is challenging. Further study of this strategy can therefore be of benefit to a wide spectrum of cancer patients.

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