Emerging Target, “Cell Metabolism”: From Boondocks to Harvard Square, Boston

The emergence of “cancer energy metabolism” as one of the promising targets, is affirmed by the two significant Pharma deals this year:
Early this year in April, Celgene opened its wallets to the tune of $130 million in upfront fees for potential drug candidates coming out of Agios.[read more at invivoblog]  And recently in September, AstraZeneca and Cancer Research UK (CRUK) signed a partnership deal under the charity’s development and commercialization arm, Cancer Research Technology (CRT), to develop novel cancer metabolism drugs.  CRT will test AstraZeneca’s AZD-3965 in phase I/II trials; and after the results are in, AstraZeneca may decide if it wants to develop the drug further, otherwise, CRUK, if it wants, will be free to partner with others and bring the drug to clinic.  AZD-3965 targets the monocarboxylate transporter 1 (MCT-1) which is essential in cell metabolism.  Another significant handshake not long ago, was the $780MM partnership signed in 2008 between GlaxoSmithKline and Sirtris Pharmaceuticals.  The merits of this one remain fuzzy; GSK discontinued the development of Sirtis’ SRT501 (aka resveratrol) in May this year after reports of kidney failure in multiple myeloma trial [...]  Sirtis still has >6000 compounds in its library.  The target of resveratrol, SIRT1 is an NAD(+)-dependent protein deacetylase which has a complex role in cancer.[...][...]  The cancer bioenergetics field and pharmaceutical intesrest in this target remains strong and it could turn out to be very promising over the next two-three years, particularly in developing strategies dealing with the problem of tumor escape from existing drugs.

Warburg Effect.  Cancer cells are like “Prius” with hybrid engines.  These cells, instead of breaking down the fuel (glucose) via the mitochondrial oxygen-generating engine (aka “Pasteur effect”), increasingly rely on the lactic acid generating battery.  Like “Prius,” cancer cells are smart; the lactic acid battery gives them a host of advantages: lactic acidosis triggers signaling pathways, making cells resistant to chemo or radiation, less dependent on oxygen within the hypoxic environment, and so on.  In the 1920s, German biochemist Otto Warburg established that cancer cells reprogram their glucose metabolism and utilize glucose via anaerobic pathway to generate lactic acid, even in the presence of normoxic conditions (aerobic glycolysis; Warburg effect), and in 1931, he was awarded a Nobel Prize for this discovery.  Warburg believed that mitochondrial dysfunction force cells to use aerobic glycolysis instead of beta-oxidation (OXPHOS) – this point, though, is still debatable.  Warburg hypothesis generated tremendous research interest in the biochemistry of cancer metabolism which lasted till the dawn of the DNA era (1960s).  At this point, with the discovery of cancer-causing oncogenes and tumor suppressor genes in the 1970s, the focus quickly shifted to signaling molecules and growth factors as the primary drivers and potential drug targets of cancer.  In the background, the observations, such as, Ras and p53 mutations also effecting metabolic genes, kept on popping.  Over the last decade, the concepts of Warburg effect, oncogenes signaling pathways and growth factors' role have come together in the same room - Metabolic reprogramming is driven by the same oncogenes and signaling pathways that drive cancer cell proliferation; in other words, these are coordinated processes.  “Cell Metabolism” as a target covers the whole gamut, glucose, lipid and amino acid metabolic pathways, as well as autophagy.  Cancer is as much a metabolic disease as genetic.

Fig 2, Matthew G. Vander Heiden et al. Science 2009 | FreeFullText |

Christmas Story.  We love stories with heroes charting their own ways.  One story of the resurgence of pharmaceutical interest in cancer metabolism can be traced to the work of Matthew Vander Heiden (now at Koch Inst, MIT) who started looking at cancer metabolism as a graduate student in the lab of Craig Thompson (then at U Chicago) in the 1990s.  Later at Lewis Cantley’s lab (Harvard), he studied pyruvate kinase M2 (PKM2), a key enzyme in the glycolytic pathway, and discovered that cancer cells preferentially use pyruvate kinase M2 isoform instead of pyruvate kinase M1 which is used by normal cells (published in March 28, 2008 issue of Nature [...][...])  Thus, targeting PKM2 which is not found in normal cells would potentially impart specificity. This was one of the key discoveries that led to the founding of  Agios Pharmaceuticals, Boston, Mass in 2009.  The focus of Agios Pharmaceuticals is discovery and development of drugs in the field of cancer metabolism.  Among its founders are leaders in the field of cancer metabolim, including Lewis C. Cantley (Harvard), Tak W. Mak (U Toronto) and Craig B. Thompson (U Penn).  The breadth of Agios efforts include sugar metabolism (glycolysis), lipid metabolism as well as autophagy (self-metabolism).  At present, Agios has two targets in the advanced stage: isocitrate dehydrogenase (IDH1) and pyruvate kinase M2 (PKM2).

Many observations over the last few years keep driving up interest in cancer metabolism as a cool strategy.  Although, Agios and similarly focused companies have the momentum, other oncology companies have also taken notice and are casting their spare or non-performing fishing lines.  Some of the interesting observations in this field are:

• Agios team found that brain-cancer-associated mutations in the enzyme isocitrate dehydrogenase 1 catalyze the reduction (rather than dehydrogenation) of L-gluatamine to 2-hydroxyglutarate (2HG) which increase by 100X.  While this "mutated IDH1" is a brain cancer target, 2HG may serve as a general efficacy biomarker for a variety of cancer therapetuics (Nature 2009).  This work was possible only using  the whole pantry of tools: large-scale profiling of hundreds of cellular metabolites, x-ray crystallography, and enzymology, and a partnership with Shanghai ChemPartner.
• Cravatt’s team at Scripps (La Jolla, Calif.) found that a key lipid metabolic pathway enzyme, monoacylglycerol lipase is involved in aggressive tumors  (Cell 2010).
• Craig Thompson’s group at UPenn, showed that glutaminolysis (breakdown of glutamine to lactate; a hallmark of cancer cells) complements the glucose metabolism of  Warburg by providing high-energy cofactors (PNAS 2007).
• Schreiber group at Broad Inst (Cambridge, Mass.), taking a systems approach, found that Ras mutations increase cells' responsiveness to glycolysis inhibitor – in other words, cancer cells with predominantly Warburg glycolysis are vulnerable (PNAS 2005)
• Andrew Pollack summarizes in the November 30, 2010, NYTimes article, “People with Type 2 diabetes tend to have a higher risk of getting certain cancers. And preliminary evidence suggests that metformin, the most widely used diabetes pill, might be effective in treating or preventing cancer.”  Although, he goes on to caution that the connection between cancer and diabetes may be due to high insulin and not due to high glucose; the jury is still out. (read the article here)
• Valeria Fantin el al. (in Philip Leder’s lab at Harvard) showed that attenuation of LDH-A expression (shRNA knockdown) in neu-initiated mammary tumor cells, interferes with the ability of cells to convert glucose-derived pyruvate into lactate and shuts down tumor growth in animal models (Cancer cell 2006) “......In comparison to parental tumor cells, those clones with decreased LDH-A activity that are still capable of proliferating under normoxia exhibited a severe growth defect under hypoxic conditions in vitro. Previous work has shown that overexpression of LDH-A alone is not sufficient to induce malignant transformation (Lewis et al., 2000). However, the LDH-A dependency of Myc-transformed cells for in vitro proliferation under anaerobic conditions as well as for soft agar clonogenicity has been clearly established (Shim et al., 1997). Our results showed that LDH-A deficiency significantly compromised the tumorigenic potential of neu-initiated tumor cells transplanted into mice. At the cellular level, limiting LDH-A activity led to an increase in the rate of oxygen consumption, which was accompanied by a decrease in mitochondrial membrane potential. LDH-A-deficient cells failed to significantly accumulate the lipophilic cation F16, which preferentially concentrates in cells with elevated mitochondrial membrane potential.”
• Another molecule in late stage is MCT1 (read: Cancer's fuel duel by: Michael J. Haas SciBX 2008 December 18;1(45): 1-4 | DOI |)

The Future Drugs:

Reprogramming of cell metabolism – this smells like anti-VEGF Avastin which was originally designed to obliterate cancer blood vessels but is now known to “normalize” them – i.e., from tortuous leaky to normal-like meshwork – and as a consequence, makes the other therapies, like chemo, more effective.

The old fashioned thinking of “blocking over-expressed enzymes” is in-part a Hail Mary shot.  Yes, destroying the metabolic gears and levers may make cancer cells more susceptible to killing by immune cells, chemo, and other anti-cancer drugs, but this strategy is also prone to off-target (which could be nasty!) effects.  Alternatively, one may get unintended benefits of interfering with cancer signaling pathways because many of the glycolytic and metabolic pathway enzymes/receptors/proteins are also “moonlighting proteins.”  Teasing out all these mechanisms is what will keep the R&D excited and busy for years (if the company has enough resources to keep going.)

The exciting thing (though scary for business planners who hate unknowns) is that the drug development in this area is like going on a giant fishing trip.  The grounds are fertile – the fish aplenty – and there "will" be a catch – but, what size (!) and will it bag the top prize – that remains to be seen.

 Fig 3, Matthew G. Vander Heiden et al. Science 2009 | FreeFullText |

_____________________________________________________

Others (besides Agios) swimming in the same pond:

Cornerstone Pharmaceuticals, Inc. came on the scene much earlier than Agios.  Two of its founders,  Paul M. Bingham and Zuzana Zachar (SUNY, Stony Brook) have been looking at cancer energetics since the 1990s.  The company’s lead compound CPI-613 was granted an orphan drug status by FDA for pancreatic cancer, and is already in Phase I/II trials.  CPI-613 emerged from Cornerstone's Altered Energy Metabolism Directed (AEMD) technology platform developed in the labs of Paul M. Bingham and Zuzana Zachar.  Cornerstone Pharmaceuticals along with Agios Pharmaceuticals, recently won grants from Qualifying Therapeutic Discovery Project (QTDP) Program (under the Patient Protection and Affordable Care Act of 2010.)

Threshold Pharmaceuticals’ 2-deoxyglucose (2DG) did not work in early trials.  But, Waldemar Priebe of M.D. Anderson Cancer Center, has developed a method to deliver higher levels of this toxic compound to tumors, and licensed the technology to Intertech Bio.

Evangelos Michelakis (U Alberta) is taking the approach of providing extra energy to tumors, which then end up committing suicide.  His focus is dichloroacetate (DCA) which inhibits pyruvate dehydrogenase and shunts glucose metabolism towards mitochondria.  This compound with a checkered history needs a separate blog post!!

Dynamix also has drug programs targeting Pyruvate Kinase M2 (PKM2).

ScheBo Biotech AG from Giessen in Germany had developed and is promoting commercial PKM2 kits for colon cancer screening.  The levels of PKM2 are higher in cancer patients and is a fecal metabolic marker for colon cancer.

Advanced Cancer Therapeutics’s small molecule 3PO blocks glucose uptake –target is PFKFB3

Myrexis, Inc. (Nasdaq:MYRX) compound, MPC-9528 is a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor.  NAMPT catalizes the formation of nicotinamide adenine dinucleotide (NAD).  Depletion of NAD inhibits cell metabolism, DNA repair and other processes.  Human trials are expected in 2011.

Warburg Glycomed GmbH is developing butanoic acid derivatives which have been shown to reprogarm cancer cells’ aerobic glucose metabolism, and anti-cancer effect in vitro and in rat models.

Synta Pharmaceuticals’ Elesclomol is in early trials for ovarian cancer and in acute myeloid leukemia.  It target cancer cell energy production in the mitochondria.  Synta’s website desctibe its mode of action, “Elesclomol binds copper in plasma, which causes a change in conformation that enables its uptake through membranes and into cells. Elesclomol binds copper in an oxidative (positively charged) state called Cu(II). Once inside mitochondria, an interaction with the electron transport chain reduces the copper from Cu(II) to Cu(I), resulting in a cascade of redox reactions, a rapid increase of oxidative stress, disruption of mitochondrial energy production, and the initiation of the mitochondrial apoptosis pathway. Mitochondria generate energy for cells, but also can induce apoptosis under certain conditions, such as a high level of oxidative stress. By sensitizing mitochondria and reducing barriers to apoptosis, elesclomol may provide a means to overcome resistance to traditional chemotherapy or targeted therapy. Cancer cell mitochondria can be selectively targeted by elesclomol because cancer cell mitochondria are structurally and functionally different from their normal counterparts, making them more susceptible to changes to mitochondrial metabolism. Trials of elesclomol are currently being initiated in ovarian cancer and in acute myeloid leukemia.

Tavargenix GmbH (www.tavergenix.de) is developing inhibitors of Transketolase-like-1 (TKTL1).  TKTL1, which is high in certain tumors, such as, head and neck, promotes glucose-to-lactic acid conversion; inhibition of TKL1 results in inhibition of cancer cell proliferation and tumors in animal models. (Clin Cancer Res 2010)

Lactate Dehydrogenase A is also a target of interest [see PNAS 2010 Feb 2, 107 (5) :2037 and  Molecular cancer therapeutics 2009 March, 8(3):626]

Further Readings/Resources:

The metabolism of tumours by: Otto H. Warburg and Frank Dickens (1930) | GoogleBooks |

Abnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL-positive cells. Douglas J. Kominsky, et. al Clinical Cancer Research 2009;15(10): 3442-3450 | DOI |

Cancer's fuel duel by: Michael J. Haas SciBX 2008 December 18;1(45): 1-4 | DOI |

Why do cancers have high aerobic glycolysis? Robert A. Gatenby, Robert J. Gillies. Nature Reviews. Cancer, 2004;4(11): 891-899. | DOI |

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Matthew G. Vander Heiden, Lewis C. Cantley, Craig B. Thompson. Science, 2009;324(5930):1029-1033. | DOI |

Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Ralph J. DeBerardinis, et al., Craig B. Thompson. PNAS 2007;104(49):19345-19350. | DOI |

The Warburg Effect Is Genetically Determined in Inherited Pheochromocytomas. Judith Favier, et al., Anne-Paule Gimenez-Roqueplo. PLoS ONE, 2009;4(9):e7094. | DOI