In 2018, we published a Curious Dr. George post featuring Thomas N. Seyfried, PhD, about cancer possibly being mostly a metabolic—rather than genetic—disease. Since then, the field of cancer genomics has expanded enormously, and we have published many posts in support of better understanding and treatment of many types of cancer based on the genomic approach. Here, Dr. Seyfried and two of his colleagues at Boston College—Derek Lee, MS, and Tomás Duraj, MD, PhD—provide an update on their perspective.

Curious Dr. George: Our recent Curious Dr. George post on pancreatic cancer stimulated you to push back on existing therapeutic strategies that have been failures for so long, and suggest an entirely different approach. Why do the current treatments of pancreatic cancer fail, and what new approach might be worth considering?

Thomas N. Seyfried, PhD; Derek Lee, MS; and Tomás Duraj, MD, PhD: Current therapeutic approaches for managing the most common form of pancreatic cancer (pancreatic ductal adenocarcinoma , or PDAC)—and many other cancers, for that matter—have failed to significantly reduce deaths in severe cases. The promise of effective precision medicine based on the somatic mutation theory of cancer has not been realized. This is evident from the latest statistics published by the American Cancer Society showing that, every day, almost 1,700 people die of cancer or cancer-treatment-related causes. While it is understandable and important to highlight recent advancements, the long-term (10-year) survival rate for PDAC is still less than 5%.

It is also important to be realistic about the side effects of many first-line treatments for PDAC. Many of the current “targeted” treatments can result in severe fatigue, gastrointestinal disturbances, liver failure, and myriad other complications. These adverse effects are unacceptable and contribute further to the physical and mental stress already associated with a cancer diagnosis. Treatment modalities based on an incorrect theory of cancer origin will not provide optimal management for most patients.

In contrast to the somatic mutation theory, the mitochondrial metabolic theory can better explain the origin of cancer and provide more rational therapeutic strategies for management. For example, KRAS mutations negatively impact oxidative phosphorylation (OxPhos), thus forcing tumors to be more dependent on aerobic fermentation than on OxPhos for driving dysregulated growth. OxPhos inefficiency coupled to energy synthesis through aerobic glucose and glutamine-dependent fermentation is now recognized in nearly all cancers. Unfortunately, the metabolic dependencies of cancer cells are just an afterthought, if considered at all.

We have yet to find a report showing any cancer cells that can grow in the absence of glucose and glutamine. Ketone bodies and fatty acids are non-fermentable fuels and cannot therefore replace either glucose or glutamine for sufficient energy production in cancer cells with OxPhos insufficiency. An effective non-toxic therapeutic strategy for managing cancer would therefore involve the simultaneous down-regulation of the glucose-driven glycolysis and the glutamine-driven glutaminolysis pathways using diet-drug combinations, while transitioning the body to non-fermentable fuels, e.g., fatty acids and ketone bodies.

A transition of the body from glucose to nutritional ketosis—glucose/ketone index (GKI) values of 2.0 or below—will induce significant physiological stress on the already metabolically inflexible cancer cells while, at the same time, providing an efficient energy source for healthy cells that evolved to transition from glucose to ketone bodies under dietary energy reduction. A combination of both carbohydrate restriction and high-intensity exercise will stimulate glucose and glutamine clearance from circulation.

Adherence to this approach can be challenging for some, but shifting the role of the patient from passive observer to active participant in their non-toxic metabolic treatment strategy will help enable longer-term management of their cancer.

Dr. Seyfried can be reached at thomas.seyfried@bc.edu, Dr. Lee at leebig@bc.edu, and Dr. Duraj at tomas.duraj@bc.edu.

Additional references for successful application of ketogenic metabolic therapy in animals and humans:

İyikesici MS, Slocum AK, Slocum A, Berkarda FB, Kalamian M, Seyfried TN.Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer. Cureus. 2017 Jul 7;9(7):e1445. doi: 10.7759/cureus.1445.

Elsakka AMA, Bary MA, Abdelzaher E, Elnaggar M, Kalamian M, Mukherjee P, Seyfried TN. Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up. Front Nutr. 2018 Mar 29;5:20. doi: 10.3389/fnut.2018.00020.

Augur ZM, Doyle CM, Li M, Mukherjee P, Seyfried TN. Nontoxic Targeting of Energy Metabolism in Preclinical VM-M3 Experimental Glioblastoma. Front Nutr. 2018 Oct 5;5:91. doi: 10.3389/fnut.2018.00091. eCollection 2018.

Mukherjee P, Augur ZM, Li M, Hill C, Greenwood B, Domin MA, Kondakci G, Narain NR, Kiebish MA, Bronson RT, Arismendi-Morillo G, Chinopoulos C, Seyfried TN. Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. Communications Biol. 2019 May 29;2:200. doi: 10.1038/s42003-019-0455-x.

Seyfried TN, Shelton L, Arismendi-Morillo G, Kalamian M, Elsakka A, Maroon J, Mukherjee P. Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma? Neurochem. Res. 2019 Apr 25. doi: 10.1007/s11064-019-02795-4.

Seyfried TN, Mukherjee P, Iyikesici MS, Slocum A, Kalamian M, Spinosa JP, Chinopoulos C. Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer. Front Nutr. 2020 Mar 11;7:21. doi: 10.3389/fnut.2020.00021.

İyikesici MS, Slocum AK, Winters N, Kalamian M, Seyfried TN. Metabolically Supported Chemotherapy for Managing End-Stage Breast Cancer: A Complete and Durable Response. Cureus. 2021 Apr 26;13(4):e14686. doi: 10.7759/cureus.14686.PMID: 33927959.

Seyfried TN, Shivane AG, Kalamian M, Maroon JC, Mukherjee P, Zuccoli G. Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report. Front Nutr. 2021 May 31;8:682243. doi:10.3389/fnut.2021.682243. eCollection 2021.PMID: 34136522.

Seyfried TN. The effects of diet on prostate cancer outcomes. Nat Rev Urol. 2022 Jul;19(7):389-390. doi: 10.1038/s41585-022-00612-2.PMID: 35676538.

 

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When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks kidney cancer expert David J. Einstein, MD, how he would handle his own hypothetical case of kidney cancer. Dr. Einstein is Assistant Professor of Medicine in the Genitourinary Oncology Program at Harvard Medical School’s Beth Israel Deaconess Medical Center.

Curious Dr. George: Please consider this hypothetical scenario—you are an active clinical oncologist in general good health. But lately you have been feeling a little more tired than usual and have lost a bit of weight without dieting, so you decide to visit your primary care physician for a checkup. On physical examination, you are within normal limits, but a routine urinalysis demonstrates microscopic hematuria. A CT scan finds a rounded, 7-cm mass in the upper pole of your left kidney. On chest x-ray, one 2-cm rounded mass is found in the lower lobe of your right lung, and another similar mass is seen in the upper lobe of your left lung. How would you proceed?

David J. Einstein, MD: Before I dive into any of the oncology specifics, I would first acknowledge that this is a very difficult experience and that the most anxiety-provoking time of all is between hearing the diagnosis and learning of a treatment plan. I would definitely want to make sure that I have adequate social supports in place, understand my disability insurance and leave policies, and have access to a dedicated palliative care team to support me physically and emotionally as I embark on cancer-directed treatment.

The scenario outlined here is one of presumed metastatic disease, albeit without widespread metastases. We would first confirm that the pulmonary nodules are in fact metastatic kidney cancer with a biopsy, if feasible. We would then have a multidisciplinary evaluation. Assuming the pulmonary nodules are involved, I would think of this as “oligometastatic,” meaning a gray zone in between widely metastatic and localized.

I would start by assessing symptoms. In this case, it sounds like I have been feeling somewhat unwell, so I do need to start treatment. There are some situations in which we encounter de novo or recurrent metastatic kidney cancers that are asymptomatic and low-volume, and can sometimes be safely watched with close surveillance. We also do a clinical risk stratification. This is mostly for prognostic purposes, although there are some subtle distinctions regarding which systemic therapies are approved for which risk groups.

Then, I would be faced with the decision between systemic therapy first versus some combination of local and systemic therapy. In a situation of more widely metastatic disease, I would certainly opt for systemic therapy first, with some question of coming back to surgery later on, depending on my response and how much disease was within the kidney versus elsewhere.

In this situation, however, it may be reasonable to be aggressive with local therapies, assuming I am in good health. I would consider nephrectomy—removal of the kidney entirely—and some form of local therapy to the lung nodules, either surgery or radiation. By using all of these local therapies, we would be trying to render me disease-free, at least macroscopically. However, I would be concerned that microscopically, there could be some leftover cancer cells that could cause later recurrences. Therefore, I would consider receiving “adjuvant” immunotherapy with the goal of decreasing my risk of recurrence.

We have been using immunotherapies, especially immune checkpoint inhibitors, in metastatic kidney cancer for years. More recently, a study showed benefit for using one year of an immune checkpoint inhibitor, pembrolizumab, after surgery for patients with high-risk localized or oligometastatic kidney cancer, resulting in FDA approval. I would be receiving infusions of this every 3-6 weeks, depending on the dose, and monitoring closely for signs of excess immune activation against my own body, creating essentially an autoimmune condition. The fundamental goal here would be long-term remission, trying to be free of both cancer and treatment, for as long as possible.

Dr. Einstein can be reached at deinstei@bidmc.harvard.edu.

 

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When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks liver cancer expert Al B. Benson III, MD, FACP, FACCC, FASCO, how he would handle his own hypothetical case of liver cancer. Dr. Benson is Professor of Medicine and Associate Director for Cooperative Groups at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Curious Dr. George: Please consider this hypothetical scenario: As a busy academic oncology practitioner, you know that you contracted hepatitis C many years ago and developed chronic active hepatitis leading to fibrosis before you received sufficient Solvadi to eradicate the virus. The fibrosis led to early cirrhosis, which is now being mo

nitored by your physician. You have experienced recent weight loss and some right upper abdominal pain. Abdominal ultrasound has shown many liver nodules thought to be reactive proliferation. But your most recent serum alpha fetoprotein (AFP) has elevated to 375 ng/ml, raising the suspicion that you may now have hepatocellular carcinoma (HCC), perhaps multifocal. How would you proceed?

Al B. Benson, MD, FACP, FACCC, FASCO: I would certainly be concerned about now having a diagnosis of HCC with the known risk of having had hepatitis C, evidence of cirrhosis, and development of some symptoms. Having said that, I would recognize that the current AFP result is a bit controversial since acute inflammation and liver cell regeneration can cause an increase in AFP. It would appear that the abdominal ultrasound suggests reactive proliferation without definite evidence of HCC. Since I would be worried that the standard screening with AFP and ultrasound in my case may not have definitely ruled out HCC, I would favor proceeding with additional imaging, such as multiphasic CT scans. Once I had a contrast-enhanced abdominal CT scan I would then request review by a multidisciplinary team. If the team—particularly from the viewpoint of radiology, interventional radiology, and hepatology—agree that the lesions do not fit the criteria for HCC and are confident a biopsy would not be indicated, I would continue monitoring with very close follow-up. It would be important to make sure my liver function tests (LFTs) were not changing in terms of my cirrhosis, and there would need to be discussion as to the etiology of my symptoms.

Let us assume, however, that my CT scan fits imaging criteria for HCC. Of note. if imaging criteria are met, a biopsy would not be necessary for diagnosis, although I might still consider a biopsy—particularly for analysis by next-generation sequencing (NGS)—for the chance that there might be a molecular profile which could inform a therapeutic choice or participation in a clinical trial. If imaging was inconclusive, I would favor a biopsy to confirm the diagnosis.

Prior to a biopsy, I would want review by a transplant team as part of a multidisciplinary discussion to determine if I was a potential resection or transplant candidate, which for HCC would be my preferred treatment choice if I met the criteria for either resection or transplantation. If it was clear that resection or transplantation was not feasible, and there was no evidence of metastatic disease on CT imaging—including chest, abdomen and pelvis—then I would review with interventional radiology about the possibility of liver-directed therapy, such as Y90 radioembolization, including the possibility of participating in an available liver-directed therapy clinical trial.

Systemic therapy would be the choice if liver-directed therapy was not an option. A number of biologically driven therapies have been developed, including immunotherapy, expanding choices for individuals, with additional regimens in development in clinical trials. In my case, I would undergo an esophagogastroduodenoscopy (EGD) to evaluate presence/stability of varices, and if there is no contraindication, consider therapy with atezolizumab plus bevacizumab, with tremelimumab plus durvalumab as an alternative choice. If symptom control became an increasing issue, I would seek advice from the palliative care team.

To help friends and family better understand the management of hepatocellular cancer, I would refer them to the National Comprehensive Cancer Network (NCCN) guidelines for patients.

Dr. Benson can be reached at albenson@nm.org.

A perennial challenge in cancer treatment is figuring out how to kill tumor cells while leaving healthy cells unharmed. Our Curious Dr. George asks Stuart L. Marcus, MD, PhD, founder and Chief Science Officer at SonALAsense, how his company’s light-activated drug treatment addresses this challenge, holding potential promise for people with brain, bladder, and possibly other cancers.

Curious Dr. George: Your flagship treatment employs sonodynamic therapy (SDT), in which focused ultrasound is used to generate a light that, enabled by a metabolite of aminolevulinic acid (ALA) concentrated selectively in cancer cells, activates the oxidative destruction of those cancer cells but not other cells. How does that work? And what can you tell us about how effective it is for cancer patients?

Stuart L. Marcus, MD, PhD: To answer how SDT works, we have to first understand that SDT is a new, noninvasive form of a light-activated drug therapy called ALA photodynamic therapy (PDT). ALA PDT targets the heme pathway selectively in cancers. When provided with excess ALA, the fluorescent photosensitizer protoporphyrin IX (PpIX) accumulates primarily in cancer tissue to such a specific extent that the U.S. Food and Drug Administration (FDA) has approved ALA-induced fluorescence in a number of different cancer settings. For instance, urologists use it to help identify bladder cancers through blue light cystoscopy. Neurosurgeons also use it every day as a visual aid to resect high-grade brain cancers, such as glioblastoma multiforme (GBM), employing blue light resection and fluorescence-detecting surgical microscopes.

When PpIX is exposed to the high energies of blue light, energy is transferred from PpIX to molecular oxygen (the photodynamic process), making it highly reactive. In 1999, the FDA approved a topical ALA PDT blue light system, which I and my team at DUSA Pharmaceuticals created for treatment of the precancerous skin condition actinic keratosis. That system, now marketed by Sun Pharmaceutical Industries, has treated over 4 million people to date. ALA PDT has also been successfully used in investigational clinical studies to treat recurrent GBM (rGBM) using the ingested dye Gleolan as the source of ALA and by inserting fiber optics within the tumor which deliver laser light. Although I considered further developing PDT for rGBM, this system is so invasive and complex that, in my opinion, commercialization is moot as the treatment is very difficult to standardize.

Instead, with ALA SDT, we use MR-guided focused ultrasound to safely create light in tissue through a process called sonoluminescence. In preclinical studies, we and others have shown that this approach can effectively and selectively kill gliomas in animal models through the PDT process and boost the animals’ survival. In a first-in-man energy dose-ranging study at the Ivy Brain Tumor Center, each of 10 rGBM patients received our intravenous form of ALA, which is called SONALA-001, and we applied SDT to one-half their tumor. The patients’ tumors were surgically removed in 4 days, and oxidative changes (lipoperoxide liberation) and apoptosis were compared in the treated and untreated halves of each tumor. We found that ALA SDT selectively caused PDT oxidative damage to the treated tumor half.

We are now carrying out a therapeutic phase 2 dose-ranging clinical trial in rGBM patients. We are also treating children with the deadly cancer diffuse intrinsic pontine glioma (DIPG), in which we treat the entire brain stem. We have seen no dose-limiting toxicities as yet in either trial, attesting to the tumor-specificity of ALA. The heme pathway is a universal pathway, and the tumor-specific PpIX accumulation response to being provided with excess ALA gives us hope that SDT will prove therapeutic for many types of tumors.

Dr. Marcus can be reached at smarcus@sonalasense.com.

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When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks leukemia expert Adam Asch, MD, how he would handle his own case of acute myelogenous leukemia. Dr. Asch is Professor of Medicine and Nancy Johnson Records Chair of Oncology at the University of Oklahoma College of Medicine.

Curious Dr. George: Please consider this hypothetical scenario: You are an active clinical oncologist in general good health. But lately you have lacked energy, have been feeling a little more tired than usual, have some dizziness on exertion, have been bruising easily, and have lost a bit of weight without dieting. So, you decide to visit your primary care physician for a checkup. On physical examination, she notes that you are a little pale, finds arm bruises, and feels the tip of your spleen. She orders several lab tests. Your hematocrit is 38, hemoglobin 12, white blood cells (WBCs) are 49,000 per microliter with many blasts, many promyelocytes, myelocytes, eosinophils, and basophils. Platelets are low. A diagnosis of acute myelogenous leukemia (AML) is made. How would you proceed?

Adam Asch, MD: This would be a fascinating case to discuss in the abstract. But in the first person, as you have been exploring in your Curious Dr. George series, diagnosis and therapy take on a special and sometimes personal urgency. For this 70-year-old oncologist, the hypothetical is a timely one and for the field a relevant one, since AML is, in so many ways, a disease of aging.

For most AML patients, I find that the first, most important question to ask is if there is a curative intervention. For some, chemotherapy induction and consolidation may lead to a prolonged remission and perhaps cure. But for some disease categories—notoriously, p53-mutated disease—response to traditional chemo is poor. Second, assuming an initial remission follows an induction regimen, how a remission is consolidated is another critical question. For many people with high-risk AML (complex cytogenetics, FLT3-mutated) as well as for intermediate-risk disease, allogeneic transplant remains the best means of consolidating a remission and offering cure.

To a great extent, treatment for AML is informed by genetic and molecular studies that have become standard in the field. Cytogenetics to assess chromosomal defects, molecular analysis to identify potentially targetable mutations, and multi-channel flow cytometry to identify a blast phenotype that can be followed to assess measurable residual disease post induction and consolidation are all standard. Translocation 15;17 or “acute promyelocytic leukemia” (APL)—once considered to be the worst type of AML prognostically—is now routinely treated with all-trans retinoic acid and arsenic trioxide, with long-term survival now approaching 90%. The clinical presentation in my hypothetical case does not sound like APL, though the bruising raises the question, and the coagulation profile, if indicative of disseminated intravascular coagulation, might make that more of a question. Other good prognostic cytogenetics are translocations of 8;21 and inversion ch16. Each of these has a historical long-term survival of about 60 to 70% with standard induction chemotherapy (I’ll say another word about this in a bit). All other cytogenetic features are classified as intermediate risk or poor risk, with long term survival rates of 30-40% or 10%, respectively. For each of these latter risk groups, transplant remains the only real chance of relapse-free, long-term survival.

Now, before we discuss treatment regimens for AML in general, there are some features of my hypothetical presentation that would lead me to ask for some additional data. The presence of a spleen tip and the presence of early myeloid forms and eosinophils and basophils in addition to blasts raises the possibility that my disease is a Ph+ blast crisis rather than de novo AML. If so, treatment with a kinase inhibitor directed at the BCR-ABL kinase—after initial cytoreduction of the elevated blast count—would be a reasonable initial approach to getting control of the disease. But without allogeneic transplant as consolidation, this would not offer me long-term control of the disease. So, more on transplant in a bit.

Standard induction for “fit” patients with AML remained largely unchanged for several decades—until recently. The chemo combination of 7+3 (7days of cytosine arabinoside and 3 days of an anthracycline) has been the backbone in the U.S. of induction. Consolidation chemotherapy with 3 to 4 subsequent cycles of high-dose cytosine arabinoside has been common practice. The development of a liposomal preparation containing a defined ratio of cytosine arabinoside and daunorubicin has shown increased efficacy in AML that arises from a pre-existing condition known as myelodysplastic syndrome (MDS). Also, drugs targeting specific mutations in genes such as FLT3, IDH1, or IDH2 are additional options that can now be used in combination with standard approaches—or alone in some instances. But perhaps most impressive has been the incorporation of the BCL2 inhibitor venetoclax in combination with azacytidine as a low-intensity regimen now approved by the U.S. Food and Drug Administration (FDA) for elderly and unfit patients with MDS. Response rates appear essentially equal to those of the standard high-intensity induction regimens. Importantly, this regimen generally has lower toxicity and is most often administered outpatient. Recent data shows that patients achieving a complete response with this regimen do as well with allogeneic transplant as folks who received more intensive induction. And for younger, fit patients, venetoclax added to more intensive regimens is producing results that are likely significant improvements over the old 7+3.

So, getting back to the first question I posed, am a looking at the possibility of a cure? Possibly. It is not likely, at my age, that cytogenetics would be favorable. Complex cytogenetics and AML arising from MDS are much more prevalent. Even if this were to be a Ph+ AML blast crisis, my long-term survival would depend on allogeneic transplant as consolidation post remission.

Am I a candidate at 70 for an allogeneic transplant? Possibly. Recent studies show that arbitrary age limits on allotransplantation have virtually disappeared across transplant centers. Less ablative regimens and improved supportive care around infection control and prevention of graft-versus-host disease have led to a situation where transplantation for older patients is a viable option with reasonable outcomes. Unfortunately, it is one that is currently afforded to only about 5% of older AML patients.

So, what would I want in this situation? For my intermediate or poor-risk AML, I would likely opt for azacytidine and venetoclax as an induction/consolidation regimen, which would give me a better chance of escaping potentially debilitating complications of induction and consolidation that might put a definitive transplant out of reach. And, I would consider transplant as consolidation if in complete remission and still in good shape.

Some reality here: if these approaches didn’t get me to a complete remission, my discussions would center on defining the best way to preserve quality of life with family and friends during my remaining time.

Dr. Asch can be reached at adam-asch@ouhsc.edu.

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