Monday, October 31, 2011

How the Evil Doctor Doofenshmirtz is Bringing Cancer Metabolic Addiction to the Tri-State Area

A Senior VP of a Bay Area cancer biotech's R&D recently gave a spin to an old saying and commented, “the beatings will continue until the patient body's morale will improve,” and he added, “the beating will now come through cancer cell metabolism."  
When I asked him to elaborate, he paused, took a sip of his favorite latte concoction, and said that the beaten are the "cancer cells, " the morale is the "patient's immune system," the ones doing the beating will be the new approaches targeting cancer metabolism, and the pioneers are the likes of Agios.  Clearly, he had great faith in the strategy targeting cancer cell metabolism.

While our conversation at the cafe drifted to other topics, when I got home, I saw a copy of the September 2011 issue of Nature Reviews Drug Discovery in my mailbox—the cover had a picture of a half-opened window with a caption: "Targeting Cancer Metabolism: A therapeutic window opens."

  • How far has our understanding of cancer metabolism come? 
  • How much we know about this particular Achilles heel and where can we take an advantage?  
These are some the questions probed in Mathew Heiden's review in the September 2011 issue of Nature Reviews Drug Discovery.
There is more to cancer cell metabolism than what meets the eye

The central message of Heiden's review which many of us have forgotten is that the concept of cancer cell metabolism goes beyond Warburg effect.  It includes not only aerobic glycolysis, but also alterations in nucleic acid synthesis, amino acid metabolism and protein synthesis, TCA cycle/mitochondrial metabolism, lipid and fatty acid synthesis, and NAD metabolism—bringing this concept to the reader's consciousness is like the creation of the Department of Homeland Security, bringing together numerous parts apparently working in separate silos into a single room.

Heiden also reminds us that metabolic alterations in cancer cells are just adaptations driven by underlying gain or loss of function mutations. Under the hood, it's just genetic alterations! Often the Drs. Heinz Doofenshmirtzes are Ras and Myc genes—the very genes discovered during the dawn of cancer oncogene era, and yet, intractable targets so far.  But now, by pointing the laser on cancer “addiction” of alternate metabolic pathways, for the very first, we can actually target these basic cancer oncogenes.

Other highlights of Heiden's review:
  • Comprehensive list of metabolic enzymes and pathways (i.e., targets) where evidence (preclinical, Phase 1 or 2) is current available.
  • Targeting cell metabolism is another way to target cancer microenvironment. Tumors often have hypoxic cores favoring anerobic environment and cancer metabolic adaptations.
  • Drugs targeting nucleic acid synthesis—such as, antifolates and nucleic acid analogs—were the first ever approved chemotherapeutics that are still in use today. Thus, the issue of “toxicity” of targeting basic cellular pathways is overblown, and it is indeed possible to find a “therapeutic window” for agents targeting cancer cell metabolism.
  • Targeting cell metabolism may potentiate existing therapies. It may help target cells which escape current drugs. I can suggest one more mechanism: Think of the way anti-VEGF drugs work. Anti-VEGF drugs like Avastin work by “normalizing” tortuous cancer vasculature allowing chemotheraputic drugs to gain access and kill tumor cells. Similarly, targeting cancer metabolic addictions may select for cells with “normalized” metabolism and expose other cancer specific targets, such as tyrosine kinases, for which we have several drugs in clinic or pipeline.
  • Our understanding of cancer metabolic addictions is already making a difference in cancer diagnosis and staging:  [18]F-deoxyglucose positron emission tomography (FDG-PET) is used for staging cancer and differentiating cancer cells from normal cells.
Challenges Remain but will be sorted out
  • Therapeutic window does not exist for all targets, for instance, a metabolic uncoupling agent 2,4-dinitrophenol (DNP)—first introduced in 1930s as wight loss agent—is lethal outside a narrow therapeutic range. However, metformin (an approved anti-diabetic agent) which also leads to metabolic uncoupling can help target anerobic metabolism; it is under clinical investigation in caner patients.
  • The biggest challenge is the lack detailed understanding of metabolic flux in cancer cells. However, newer tools to provide better description of of metabolic profiling are being developed.
Annual progress report

A little less than a year ago, I wrote a post on a similar topic, profiling Agios and other companies targeting cancer cell metabolism: "Emerging Target, 'Cell Metabolism': From Boondocks to Harvard Square, Boston."  

Here is an update on the progress made by some of these companies since the last post was written.  The only drug in clinical trial is TH-302; however, it is not truly targeting cancer metabolism!
  1. Agios Therapeutics, Cambridge, Mass., continues to make scientific progress on two targets, IDH1/2 and PKM2; however, these have not yet entered clinical testing.  Using  metabolic flux analysis technique, the company (or its collaborators) published the discovery of disregulated serine metabolic pathway in certain breast cancers (read August 2,2011 press release here).
  2. Cornerstone Pharmaceuticals' (Cranbury, NJ) lead compound CPI-613 targets mitochondrial metabolism.  There is no update on their ongoing Phase I/II trials in  lymphomas, leukemia and in combination with gemcitabine in newly diagnosed pancreatic cancer patients.   However, they did announce publication of preclinical data in the Journal of Molecular Medicine illustrating the mechanism of CPI-613 action. [click here for press release; and here for manuscript]
  3. Threshold Pharmaceuticals, Inc., Ridgefield Park, NJ, (NASDAQ: THLD) in its Sept. 30, 2011, press release disclosed that its lead compound TH-302 has entered Phase III trial inn soft tissue sarcoma in combination with doxorubicin.  This trial is being conducted in collaboration with Sarcoma Alliance for Research through Collaboration (SARC).  TH-302 is a prodrug which is activated under hypoxic conditions. [Wikipedia]
  4. TH-302 Phase I/II data (Trials TH-CR-401 and TH-CR-402 conducted between 2007-2010):  "TH-302 has been tested in over 550 patients with cancer including over 100 patients to date treated in a Phase 1/2 trial in patients with soft tissue sarcoma. As presented at theAmerican Society of Clinical Oncology meeting in June 2011, 60 patients from the Phase 2 component of the study had at least one evaluable post-treatment tumor assessment. There was one complete response (2%), 18 partial responses (30%) and 32 stable disease (53%). Median progression free survival was 6.4 months (95% confidence interval: 5.6 to 8.1 months). Median overall survival was 16.1 months (95% CI: 10.4 months to upper limit not yet reached). Just under half (47%) of patients continued to receive TH-302 alone after completing the full doxorubicin regimen of 6 cycles. Myelosuppression was dose limiting with 15% grade 4 neutropenia and 13% grade 4 thrombocytopenia. Collectively, these data contribute to the rationale for initiating the registration study." (From:  Threshold Pharmaceuticals, Inc., press release, September 30, 2011)
  5. Dynamix PharmaceuticalsRehovot, Israel, has developed a series of small-molecule PKM2 activators (DNX-03000) which target two regions of the PKM2 tetramer.  The company presented preclinical data at the AACR meeting this year.
  6. Advanced Cancer Therapeutics (ACT), Louisville, Kentucky, presented preclinical data showing anticancer effects of PFKFB3 which blocks glucose uptake by cancer cells at the AACR 2011 (press release).  Now the company is focusing on developing second generation compound PFK015.  No clinical experience yet.
  7. Myrexis, IncSalt Lake City, Utah (NASDAQ: MYRX).  MPC-8640, a NAMPT inhibitor, is an orally bioavailable prodrug (and a follow-on to MPC-9528).  This compound is still in preclinical phase with IND-enabling studies ongoing.
  8. Warburg Glycomed, Erkrath, Germany, has preclinical data on WG-001 compound, and the company is seeking cooperation or licencing partners.
  9. Synta PharmaceuticalsLexington, Mass., (NASDAQ: SNTA) their lead compound Elesclomol disrupts cancer cell energy metabolism by selectively targeting the electron transport chain in cancer cell mitochondria.  This compound is being evaluated in two trials:  A Phase II trial in ovarian cancer in combination with paclitaxel, and a Phase I trial in  in patients with relapsed or refractory acute myeloid leukemia (AML).
Company Publications and Presentations:
Agios Therapeutics:
  • Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. 
  • Jason W Locasale, et al. Nature Genetics, July 2011;43:869–874 | DOI | Abstract | Scholar |
  • Regulation of cancer cell metabolism. 
  • Rob A. Cairns, et al. Nature Reviews Cancer. February 2011; 11, 85-95 | DOI | Abstract |
Threshold Pharmaceuticals:
  • Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. Zuzana Zachar et al.  Journal of Molecular Medicine.  July 2011; 89(11):1137-1148 | DOI | Abstract |
Dynamix Pharmaceuticals:
  • Modulation of Cancer Metabolism with Novel PKM2 Activators Exerts Anti‐Tumor Activity.  AACR 2011 Poster 4065 | PDF at company website |
Advanced Cancer Therapeutics:
  • Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anti-cancer agents in vivo.  Zuzana Zacha, et al. Journal of Molecular Medicine 2011 (in press)
Myrexis, Inc.:
  • Activity of the cancer metabolism inhibitor MPC-9528 in xenograft models: Comparison of different dosing schedules.  ASCO Chicago 2011 Poster | PDF at company website |
  • Coadministration of nicotinic acid with the Nampt inhibitor MPC-9528 enhances anti-tumor activity in Naprt deficient cancer cells in culture and in xenografts. AACR Orlando 2011 Poster | PDF at company website |
  • The Nampt inhibitor MPC-9528 synergizes with DNA damaging agents. AACR Orlando 2011 Poster | PDF at company website |
  • Basal NAD levels and Nampt expression correlate with in vitro and in vivo sensitivity of tumor cell lines to the Nampt inhibitor MPC-9528. AACR Orlando 2011 Poster | PDF at company website |
Synta Pharmaceuticals:
  • Elesclomol-Cu chelate selectively targets mitochondria to induce oxidative stress. AACR Orlando 2011 Poster | PDF at company website |
  • Downregulation of thioredoxin-1 confers resistance to cisplatin and sensitivity to the ROS generating agent elesclomol. AACR Orlando 2011 Poster | PDF at company website |
*Cancer cell metabolism continues to excite scientific interest.  At the last AACR meeting, there were over 92 abstracts with the key word "metabolism." Vander Heiden MG (2011). Targeting cancer metabolism: a therapeutic window opens. Nature reviews. Drug discovery, 10 (9), 671-84 PMID: 21878982 
Abstract | DOI | Scholar | Free PDF herehere |

Related Posts:
Emerging Target, “Cell Metabolism”: From Boondocks to Harvard Square, Boston. December 16, 2010.

Happy Halloween to all readers.

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