Targeting energy metabolism in brain cancer: review and hypothesis.

Targeting energy metabolism in brain cancer: review and hypothesis.

Seyfried TNMukherjee P.

Biology Department, Boston College, Chestnut Hill, MA 02467, USA.thomas.seyfried@bc.edu

Malignant brain tumors are a significant health problem in children and adults and are often3D2 0unmanageable. As a metabolic disorder involving the dysregulation of glycolysis and respiration, malignant brain cancer is potentially manageable through changes in metabolic environment. A radically different approach to brain cancer management is proposed that combines metabolic control analysis with the evolutionarily conserved capacity of normal cells to survive extreme shifts in physiological environment. In contrast to malignant brain tumors that are largely dependent on glycolysis for energy, normal neurons and glia readily transition to ketone bodies (beta-hydroxybutyrate) for energy in vivo when glucose levels are reduced. The bioenergetic transition from glucose to ketone bodies metabolically targets brain tumors through integrated anti-inflammatory, anti-angiogenic, and pro-apoptotic mechanisms. The approach focuses more on the genomic flexibility of normal cells than on the genomic defects of tumor cells and is supported from recent studies in orthotopic mouse brain tumor models and in human pediatric astrocytoma treated with dietary energy restriction and the ketogenic diet.

PMID: 16242042 [PubMed]

PMCID: PMC1276814

Whole blueberry powder modulates the growth and metastasis of MDA-MB-231 triple negative breast tumors in nude mice

J Nutr. 2011 Oct;141(10):1805-12. doi: 10.3945/jn.111.140178. Epub  2011 Aug 31.
Whole blueberry powder modulates the growth and metastasis of MDA-MB-231 triple negative breast tumors in nude mice.
Adams LS, Kanaya N, Phung S, Liu Z, Chen S.

Source
Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, Duarte, CA, USA.

Abstract

Previous studies in our laboratory demonstrated that blueberry (BB) extract exhibited antitumor activity against MDA-MB-231 triple negative breast cancer (TNBC) cells and decreased metastatic potential in vitro. The current study tested 2 doses of whole BB powder, 5 and 10% (wt:wt) in the diet, against MDA-MB-231 tumor growth in female nude mice. In this study, tumor volume was 75% lower in mice fed the 5% BB diet and 60% lower in mice fed the 10% BB diet than in control mice (P ≤ 0.05). Tumor cell proliferation (Ki-67) was lower in the 5 and 10% BB-fed mice and cell death (Caspase 3) was greater in the 10% BB-fed mice compared to control mice (P ≤ 0.05). Gene analysis of tumor tissues from the 5% BB-fed mice revealed significantly altered expression of genes important to inflammation, cancer, and metastasis, specifically, Wnt signaling, thrombospondin-2, IL-13, and IFNγ. To confirm effects on Wnt signaling, analysis of tumor tissues from 5% BB-fed mice revealed lower β-catenin expression and glycogen synthase kinase-3β phosphorylation with greater expression of the β-catenin inhibitory protein adenomatous polyposis coli compared to controls. A second study tested the ability of the 5% BB diet to inhibit MDA-MB-231-luc-D3H2LN metastasis in vivo. In this study, 5% BB-fed mice developed 70% fewer liver metastases (P = 0.04) and 25% fewer lymph node metastases (P = 0.09) compared to control mice. This study demonstrates the oral antitumor and metastasis activity of whole BB powder against TNBC in mice.

PMID:

21880954

[PubMed – indexed for MEDLINE]

PMCID:

PMC3174855

Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism

Cancer Lett. 2012 Oct 1;323(1):29-40. doi: 10.1016/j.canlet.2012.03.031. Epub  2012 Apr 1.
Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism.
Torres MP, Rachagani S, Purohit V, Pandey P, Joshi S, Moore ED, Johansson SL, Singh PK, Ganti AK, Batra SK.

Source
Department of Biochemistry and Molecular Biology, Omaha, NE 68198-5870, USA.

Abstract

Pancreatic tumors are resistant to conventional chemotherapies. The present study was aimed at evaluating the potential of a novel plant-derived product as a therapeutic agent for pancreatic cancer (PC). The effects of an extract from the tropical tree Annona Muricata, commonly known as Graviola, was evaluated for cytotoxicity, cell metabolism, cancer-associated protein/gene expression, tumorigenicity, and metastatic properties of PC cells. Our experiments revealed that Graviola induced necrosis of PC cells by inhibiting cellular metabolism. The expression of molecules related to hypoxia and glycolysis in PC cells (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) were downregulated in the presence of the extract. In vitro functional assays further confirmed the inhibition of tumorigenic properties of PC cells. Overall, the compounds that are naturally present in a Graviola extract inhibited multiple signaling pathways that regulate metabolism, cell cycle, survival, and metastatic properties in PC cells. Collectively, alterations in these parameters led to a decrease in tumorigenicity and metastasis of orthotopically implanted pancreatic tumors, indicating promising characteristics of the natural product against this lethal disease.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

PMID:

22475682

[PubMed – indexed for MEDLINE]

PMCID:

PMC3371140
[Available on 2013/10/1]

New Cancer Agent Debuts in Multiple Cancers, ‘Living Therapy’ May Last for ‘Many Years’

New Cancer Agent Debuts in Multiple Cancers
‘Living Therapy’ May Last for ‘Many Years’
Nick Mulcahy
Apr 08, 2013

WASHINGTON, DC — In a noteworthy moment in the history of cancer drug development, phase 3 clinical trials of an experimental agent are simultaneously underway in 3 different cancer types.
Trials of the investigational immunotherapy nivolumab (Bristol-Myers Squibb) have begun in melanoma, renal cell carcinoma, and nonsmall-cell lung cancer, said Suzanne Topalian, MD, here at the annual meeting of the American Association for Cancer Research (AACR) 104th Annual Meeting. She is from the Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.
The simultaneous trials of a single investigational agent in so many different cancers “may be unprecedented,” Dr. Topalian told Medscape Medical News in an interview.
The phase 3 trials are an outgrowth of the positive results seen in phase 1 trials of nivolumab, which was previously called BMS-936558 and MDX-1106. The agent is a monoclonal antibody that neutralizes the programmed death 1 (PD-1) protein, an element of tumors that enables them to evade their nemesis, the immune system.
Nivolumab was hailed as the next big thing in cancer treatment last year after early data indicated that it had durable tumor response rates of 20% to 30% in multiple cancers. In the words of one expert, the agent had “broken the ceiling” of durable tumor response rates of 10% to 15% that has existed for cancer immunotherapies over the past 30 years.
That an immunotherapy — and not some other type of cancer treatment — should be making such an auspicious debut in phase 3 trials is not an accident, Dr. Topalian noted.
“In many ways, the adaptive immune system comprised of T-cells and antibodies is an ideal anticancer agent,” she told the audience at a plenary session.
Dr. Topalian challenged the prevailing wisdom in cancer research.
“The current dogma is that cancer is a genetic disease,” she explained, acknowledging that individual tumors contain hundreds of mutations and alterations in signaling pathways, which are the basis of the personalized medicine approach.
But the genetic model is highly problematic, she argued. The problem of resistance to targeted therapies “has its limitations,” she noted. “Blocking one pathway can lead to the emergence of another,” she explained.
An “alternative viewpoint” proposed by Dr. Topalian is that “cancer is an immunologic disorder.”
Immunotherapy is the “common denominator” that “takes advantage of the fact that many of the mutations of cancer can be specifically recognized and targeted by the immune system.” Furthermore, “the immune system can adapt and evolve as the cancer evolves,” she said.
Dr. Topalian showed a timeline  of the identification of the PD-1 gene and the development of an anti-PD-1 therapy (Nat Immunol. 2012;13:1129-1132). The timeline, which was not created by her research team, projects US Food and Drug Administration approval of anti-PD-1 therapies by 2015.
“If nivolumab is approved, it would be so inspiring and motivating for the field of immunology,” said Priyanka Agharkar, a predoctoral trainee from the Department of Cell Stress Biology at the Roswell Park Cancer Institute in Buffalo, New York. Aside from sipuleucel-T (Provenge) for prostate cancer and ipilimumab (Yervoy) for melanoma, “there is very little approved in terms of immunotherapies for cancer,” she told Medscape Medical News.
There is now plenty of competition in the field of anti-PD-1 agents and complementary anti-PDL1 agents. In fact, Genentech, Amplimmune/GSK, CureTech, Merck, and MedImmune all have drug development programs.
Proof From 3 Patients That the Immune System Has “Memory”
The quality that makes the immune system “different from all other cancer therapies” is that the immune system has “memory,” said Dr. Topalian.
To support her assertion, she showed treatment and response timelines for 3 of 39 patients treated with nivolumab in the first-in-human trials for melanoma, renal cell carcinoma, nonsmall-cell lung cancer,   prostate cancer, and colorectal cancer.
The 3 patients had objective responses for a “very long time” after a single course of treatment with nivolumab, she reported.
A patient with colorectal cancer had a complete response after a few months of treatment, which has remained   into year 4 after initiation of treatment.
A patient with kidney cancer had a partial response after a few months of treatment; the tumor continued to shrink and a complete response was seen in year 3 after treatment. The patient has maintained the response into year 4.
A melanoma patient had a partial response and was taken off treatment after a few months. In year 3 after trial enrollment, that patient had lymph node metastases and resumed treatment, but has achieved an ongoing partial response into year 4.
In addition, in a follow-up phase 1 trial of nivolumab, durable tumor regressions were seen in approximately 300 patients with lung cancer, melanoma, and kidney cancer, and regressions persisted even after the drug was discontinued.
These results are “compatible” with the idea that the immune system has a memory, said Dr. Topalian.

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“This is actually a living therapy that stays with the host, potentially for years,” she noted.
She explained that the duration of the effect could be similar to childhood vaccines for infectious diseases, and the resulting immunity might even last a lifetime.
Dr. Topalian reports a financial relationship with Bristol-Myers Squibb.
American Association for Cancer Research (AACR) 104th Annual Meeting. Presented April 7, 2013.

Screening Blood Samples for Cancer-Driving Mutations More Comprehensive Than Analyzing Traditional Tumor Biopsy

Screening Blood Samples for Cancer-Driving Mutations More Comprehensive Than Analyzing Traditional Tumor Biopsy

Apr. 6, 2013 — Researchers using a tool called BEAMing technology, which can detect cancer-driving gene mutations in patients’ blood samples, were able to identify oncogenic mutations associated with distinct responses to therapies used to treat patients with gastrointestinal stromal tumors (GIST), according to a researcher who presented the data at the AACR Annual Meeting 2013, held in Washington D.C., April 6-10.

Data from a subanalysis of the phase III GIST-Regorafenib In Progressive Disease (GRID) trial indicated that this blood-based screening technology may provide physicians with a real-time, comprehensive picture of a patient’s tumor mutations, according to George D. Demetri, M.D., director of the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School in Boston, Mass.
“Our results show that it is possible to sum the total of all of the heterogeneity in a cancer and get a clear picture of the entire tumor burden, using a simple blood sample,” Demetri said.
In this era of targeted cancer therapies, the goal is to focus cancer treatments on a specific molecular target. However, as researchers discover more about cancers and their heterogeneity, they are finding many patients have anywhere from one to dozens of different mutations in their tumors.
“It is a real issue that when you do a biopsy on one tumor, and then biopsy a different tumor in that same patient a few inches away or on the other side of the body, you may get a different answer when you do the molecular analysis,” Demetri said. “With this blood test, you get a robust summary statement about all the different mutations present across the different tumors in the body. I believe this testing technology has promise to become a standard part of care in the next five to 10 years.”
Data from the main analysis of the phase III GRID study showed that the molecularly targeted drug regorafenib significantly improved progression-free survival compared with placebo for patients with GIST. The researchers hope these results will ultimately lead to the drug’s approval by the U.S. Food and Drug Administration (FDA), according to Demetri. The drug is intended to treat patients with advanced GIST whose disease has failed to be controlled by the only two other FDA-approved therapies for GIST, imatinib and sunitinib (Sutent).
Demetri and colleagues conducted an exploratory analysis on patients in the GRID study to assess GIST genotypes. They isolated DNA from archival tumor tissue, which was then analyzed for mutations in two genes, KIT and PDGFRA, which generate the cancer-driving proteins that are the targets of imatinib, sunitinib and regorafenib. The researchers believed that primary mutations would be detectable using traditional analysis, but that those mutations that developed after treatment with imatinib and sunitinib would not be detectable. They then took blood samples drawn at study entry after failure of both imatinib and sunitinib, and analyzed them for mutations via BEAMing technology.
Mutations in the KIT gene were detected in 60 percent of the blood samples compared with 65 percent of the tumor tissue samples. However, when focusing their analysis on secondary KIT mutations, which are the mutations that drive resistance to targeted therapies like imatinib and sunitinib, the researchers found mutations in 48 percent of blood samples compared with only 12 percent of tissue samples. In addition, nearly half of blood samples in which secondary KIT mutations were found harbored multiple secondary mutations.
Importantly, regorafenib was clinically active compared with placebo in patients with secondary KIT mutations.
According to Demetri, the results show a clear association between the presence of different cancer-driving gene mutations in patients’ blood samples and clinical outcomes.
“By using this technology, we hope to develop the most rational drug combinations and better tests to match patients with the most effective therapies going forward,” Demetri said.

Antineoplastic effects of melatonin on a rare malignancy of mesenchymal origin: melatonin receptor-mediated inhibition of signal transduction, linoleic acid metabolism and growth in tissue-isolated human leiomyosarcoma xenografts

al Res. 2009 Aug;47(1):32-42. doi: 10.1111/j.1600-079X.2009.00686.x. Epub  2009 May 27.
Antineoplastic effects of melatonin on a rare malignancy of mesenchymal origin: melatonin receptor-mediated inhibition of signal transduction, linoleic acid metabolism and growth in tissue-isolated human leiomyosarcoma xenografts.
Dauchy RT, Blask DE, Dauchy EM, Davidson LK, Tirrell PC, Greene MW, Tirrell RP, Hill CR, Sauer LA.

Source
Laboratory of Chrono-Neuroendocrine Oncology, Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, Louisiana Cancer Research Consortium, New Orleans, LA 70112-2699, USA. rdauchy@tulane.edu

Abstract

Melatonin provides a circadian signal that regulates linoleic acid (LA)-dependent tumor growth. In rodent and human cancer xenografts of epithelial origin in vivo, melatonin suppresses the growth-stimulatory effects of linoleic acid (LA) by blocking its uptake and metabolism to the mitogenic agent, 13-hydroxyoctadecadienoic acid (13-HODE). This study tested the hypothesis that both acute and long-term inhibitory effects of melatonin are exerted on LA transport and metabolism, and growth activity in tissue-isolated human leiomyosarcoma (LMS), a rare, mesenchymally-derived smooth muscle tissue sarcoma, via melatonin receptor-mediated inhibition of signal transduction activity. Melatonin added to the drinking water of female nude rats bearing tissue-isolated LMS xenografts and fed a 5% corn oil (CO) diet caused the rapid regression of these tumors (0.17 +/- 0.02 g/day) versus control xenografts that continued to grow at 0.22 +/- 0.03 g/day over a 10-day period. LMS perfused in situ for 150 min with arterial donor blood augmented with physiological nocturnal levels of melatonin showed a dose-dependent suppression of tumor cAMP production, LA uptake, 13-HODE release, extracellular signal-regulated kinase (ERK 1/2), mitogen activated protein kinase (MEK), Akt activation, and [(3)H]thymidine incorporation into DNA and DNA content. The inhibitory effects of melatonin were reversible and preventable with either melatonin receptor antagonist S20928, pertussis toxin, forskolin, or 8-Br-cAMP. These results demonstrate that, as observed in epithelially-derived cancers, a nocturnal physiological melatonin concentration acutely suppress the proliferative activity of mesenchymal human LMS xenografts while long-term treatment of established tumors with a pharmacological dose of melatonin induced tumor regression via a melatonin receptor-mediated signal transduction mechanism involving the inhibition of tumor LA uptake and metabolism.

PMID:

19486272

[PubMed – indexed for MEDLINE]

Fatty Acid Metabolite Shows Promise Against Cancer in Mice

Fatty Acid Metabolite Shows Promise Against Cancer in Mice

Apr. 2, 2013 — A team of UC Davis scientists has found that a product resulting from a metabolized omega-3 fatty acid helps combat cancer by cutting off the supply of oxygen and nutrients that fuel tumor growth and spread of the disease.

The scientists report their discovery in the Proceedings of the National Academy of Sciences (PNAS). The groundbreaking study was a collaboration among multiple UC Davis laboratories and Harvard University.
The metabolite is epoxy docosapentaenoic acid (EDP), an endogenous compound produced by the human body from the omega-3 fatty acid named docosahexaenoic acid (DHA), which is found in fish oil and breast milk. In animal studies, the UC Davis scientists found that EDP inhibits angiogenesis, the formation of new blood vessels in the body.
Tumors grow and spread by hijacking the normal biological process of angiogenesis, which plays a role in wound repair as well in growth and development. The UC Davis researchers determined that by inhibiting angiogenesis, EDP reduces the growth and spread (metastasis) of tumors in mice. The research provides the first scientific evidence about EDP’s potent anti-cancer, anti-metastatic effects.
EDP works by a different mechanism than many current anti-cancer drugs that block angiogenesis. “Our investigation opens up a new understanding of the pathways by which omega-3 fatty acids exert their biologic effects,” said Guodong Zhang, the lead author of the article and a postdoctoral researcher in the laboratory of Bruce Hammock in the Department of Entomology and the UC Davis Comprehensive Cancer Center.
The researchers said that future studies hopefully will determine that stabilized EDP can be safely and effectively combined with other current anti-angiogenesis drugs in the treatment of cancer.
“As far as we know, EDPs are the first signaling lipids that have been discovered to have such potent anti-cancer effects. Researchers may be able to use EDPs as structural targets to develop stable analogs that mimic their anti-cancer agents,” Zhang said.
“The study by Zhang and colleagues has uncovered a previously unrecognized anti-cancer effect of omega-3 fatty acids, which are an important lipid component of diets that have been developed to prevent heart disease and cancer,” said Jonathan R. Lindner, professor of medicine at Oregon Health & Sciences University.
“The authors have demonstrated that metabolites of these lipids can act to suppress the growth of new blood vessels that are necessary to feed tumor growth,” added Lindner, who was not involved in the study. “By shutting off a tumor’s blood supply, these compounds can act to dramatically slow tumor growth and prevent spread.  The results from this study suggest that new drug strategies for fighting cancer could emerge from knowledge of how the body uses nutrition to promote health.”
The EDPs are broken down in the body by inhibiting the enzyme soluble epoxide hydrolase (sHI). In previous research, Hammock’s lab showed that inhibitors of the sEHI enzyme help to normalize physiological activity. In the current study, UC Davis researchers determined that the addition of sEHI stabilized EDP in circulating blood thereby producing EDPs’ anti-tumor effects.  The anti-cancer drugs sorafenib and regorafenib are FDA-approved sEHIs.
“It may be possible to improve the efficacy of these anti-cancer drugs by combining them with a diet high in omega-3 and low in omega-6 fatty acids,” Hammock said.
The researchers also found that a metabolite of arachidonic acid (ARA), an omega-6 fatty acid, has the opposite effect of EDP. The ARA metabolite, epoxyeicosatrienoic acids (EETs), slightly increases angiogenesis and tumor progression in mice.
“There is no free lunch,” said Katherine W. Ferrara, professor in the UC Davis Department of Biomedical Engineering. “The EETs encourage wound healing, while the EDPs block the growth and metastasis of solid tumors.
“Our results designate EDPs and EETs as unique mediators of an angiogenic switch to regulate tumorigenesis,” Ferrara said. “They also implicate a novel mechanistic linkage between omega-3 and omega-6 fatty acids and cancers.”
UC Davis scientists determined that EDP starves tumors by inhibiting vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2)-induced angiogenesis in mice. In laboratory cultures, EDP also suppresses the endothelial cell migration needed for new blood vessels.
Thus, EDP-based angiogenesis inhibitors offer an advantage over angiogenesis inhibitors that target the VEGF-VEGFR2 pathway, which increase patients’ risk for developing high blood pressure.
Because EDPs widen the blood vessels, a medication based on the UC Davis researchers’ discovery should not increase the patient’s risk for high blood pressure.
Harvard researchers Mark Kieran and Dipak Panigrahy conducted the metastasis studies. The in vivo imaging work that allowed the scientists to monitor tumors in living mice was done in Ferrara’s UC Davis laboratory.