Yale J Biol Med. 2012 Sep;85(3):417-9. Epub 2012 Sep 25.
A report of the James Watson lecture at Yale University.
Abstract
In March 2012, Nobel Prize winner James Watson gave a seminar at Yale University entitled "Driven by Ideas." In his lecture, Watson
discussed his personal vision for the future of science, specifically
addressing how the scientific community should approach developing
anticancer agents. He discussed the use of glycolytic inhibitors as
anticancer agents due to the Warburg effect, as well as the benefits of metformin and anti-inflammatory drugs to help prevent cancer. He also compared drugs that target cell proliferation instead of targeting cell growth. Additionally, Watson commented on the mechanisms for how research should be conducted in the laboratory.
KEYWORDS:
James Watson; Warburg effect; cancer; cell proliferation; inflammation; metforminOxidants, antioxidants and the current incurability of metastatic cancers.
Watson J1.
Abstract
The vast majority of all agents used to directly kill cancer
cells (ionizing radiation, most chemotherapeutic agents and some
targeted therapies) work through either directly or indirectly
generating reactive oxygen species that block key steps in the cell
cycle. As mesenchymal cancers evolve from their epithelial cell
progenitors, they almost inevitably possess much-heightened amounts of
antioxidants that effectively block otherwise highly effective oxidant
therapies. Also key to better understanding is why and how the
anti-diabetic drug metformin
(the world's most prescribed pharmaceutical product) preferentially
kills oxidant-deficient mesenchymal p53(- -) cells. A much faster
timetable should be adopted towards developing more new drugs effective
against p53(- -) cancers.
Bet the LI combination therapy, safe, cheap and inexpensive and supported by even a cursory search of pubmed.org
got cancer, take metformin and aspirin. selectively kills cancer cells, and thus gives you more time to decide who you might wish to kill or how you might better spend your time than paying for Michael's JUNK.
for a nonimal price in the millions Dr Denise L Faustman might sell you the peptide to cure autoimmune diseases. sadly there is little incentive to sell something that works rather than something that does not work well and costs alot.
the most utilized medicine of modern times is Hiram Maxim's guaranteed cure for all ills. A shot of lead to the head from an automatic dispenser. Used all over the world with good results, the machine gun has cured man of whatever ails him.
on a more serious not see
Result Filters
Mol Carcinog. 2015 Feb 7. doi: 10.1002/mc.22284. [Epub ahead of print]
Autophagy and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha kinase (eIF2α) pathway protect ovarian cancer cells from metformin-induced apoptosis.
Abstract
Metformin, an oral biguanide for the treatment of type II diabetes, has been shown to have anticancer effects in ovarian cancer. Energy starvation induced by metformin causes endoplasmic reticulum stress-mediated unfolded protein response (UPR) and autophagy. UPR and autophagy act as a survival or death mechanism in cells. In this study, we observed that metformin-induced apoptosis was relieved by autophagy and the PERK/eIF2α pathway in ovarian cancer cells, but not in peripheral blood mononuclear cells (PBMC) or 'normal' ovarian surface epithelial cells (OSE). Increased PARP cleavage and increased LC3B-II with ATG5-ATG12 complex suggested the induction of apoptosis and autophagy, respectively, in metformin-treated ovarian cancer cells. Accumulation of acidic vacuoles in the cytoplasm and downregulation of p62 further supported late-stage autophagy. Interestingly, metformin induced interdependent activation between autophagy and the UPR, especially the PERK/eIF2α pathway. Inhibition of autophagy-induced PERK inhibition, and vice versa, were demonstrated using small molecular inhibitors (PERK inhibitor I, GSK2606414; autophagy inhibitor, 3-MA, and BafA1). Moreover, autophagy and PERK activation protected ovarian cancer cells against metformin-induced apoptosis. Metformin treatment in the presence of inhibitors of PERK and autophagy, however, had no cytotoxic effects on OSE or PBMC. In conclusion, these results suggest that inhibition of autophagy and PERK can enhance the selective anticancer effects of metformin on ovarian cancer cells. © 2015 Wiley Periodicals, Inc.Result Filters
Ann Transl Med. 2014 Jun;2(6):57. doi: 10.3978/j.issn.2305-5839.2014.06.01.
Metformin in cancer prevention and therapy.
Abstract
The
prevalence of diabetes is dramatically increasing worldwide. The
results of numerous epidemiological studies indicate that diabetic
population is not only at increased risk of cardiovascular
complications, but also at substantially higher risk of many forms of
malignancies. The use of metformin,
the most commonly prescribed drug for type 2 diabetes, was repeatedly
associated with the decreased risk of the occurrence of various types of
cancers, especially of pancreas and colon and hepatocellular carcinoma.
This observation was also confirmed by the results of numerous
meta-analyses. There are however, several unanswered questions regarding
the exact mechanism of the anticancer effect of metformin as well as its activity against various types of cancer both in diabetic and nondiabetic populations. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin and preclinical and clinical data suggesting its anticancer effect in different populations.
New Cancer Technology Gives Investors a Shot in the Arm
Immunotherapy’s promise is drawing some marquee financiers
ENLARGE
Bristol-Myers Squibb
Co.'s Yervoy melanoma treatment is among those immunotherapy drugs
fueling red-hot interest in the sector and giving new hope in the fight
against cancer.
Photo:
Bristol-Myers Squibb/Bloomberg News
Interest in the nascent approach, known as immunotherapy, has taken off following the success of Yervoy and Opdivo, a pair of drugs developed by giant Bristol-Myers Squibb Co. The treatments could generate $8.5 billion in annual revenue by 2020, Credit Suisse predicts, or more than half the New York company’s 2014 revenue of $15.9 billion.
Hopes that fledgling companies will repeat and extend upon those advances are behind the recent share-price gains in Juno Therapeutics Inc., Kite Pharma Inc. and bluebird bio Inc. Their treatments, which take a different approach than Bristol-Myers’s, haven’t yet reached the market.
“It’s clearly something new and it won’t be smooth sailing,” said Arie Belldegrun, Kite’s chairman and chief executive. “But if we can deliver what we promise, for the first time you won’t talk about remission, you can even talk about cure of cancer.”
Earlier this month, Standard & Poor’s released a report naming five cancer immunotherapy agents among its top 10 drug prospects for 2015, underscoring growing enthusiasm for the strategy. Drugs made the list for their likely blockbuster sales potential as well as their probable impact on individual companies. No such drugs were included on its previous list in 2009.
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Among companies fueling current interest, only Bristol-Myers and Merck & Co. have had immunotherapy drugs approved by the U.S. Food and Drug Administration. For many of the smaller-cap companies, it will be a year or more before studies help clarify the benefits, risks and market potential of their treatments.
Shares of Juno, which is developing therapies for leukemias and lymphomas, ended Friday’s trading at $45.52, following a December initial public offering at $24. Kite Pharma has soared to $62.80 from $28 since the beginning of October. Bluebird bio, driven more by advances by gene-therapy drugs than in immunotherapy, has climbed to $93.32 from $39 since early December.
The three companies’ treatments are complex, likely to be expensive and cause severe side effects for some patients; none has yet been approved. But the strategy has shown dramatic results in leukemia and other blood cancers in early trials and researchers are racing to find ways to extend their use to other cancers.
Indeed, researchers world-wide are working on various types of immunotherapy treatments, as well as strategies to combine them with existing treatments to tackle all kinds of cancer and extend their benefits to more patients.
Mr. Bonderman, a founder of TPG Capital, is Kite’s fourth-largest shareholder and a board member, with over 6% of the company’s stock from an early, personal investment, according to FactSet. He has seen his holdings soar to about $145 million in value.
Another early investor, hedge-fund veteran Donald Sussman, founder of Paloma Partners Management, holds a Kite stake worth about $100 million, according to regulatory filings. Representatives of Messrs. Bonderman and Sussman declined to comment.
ENLARGE
George Soros’s Soros Fund Management owns about 1.7% of Kite Pharma Inc.’s shares.
Photo:
European Pressphoto Agency
Michael Milken also was an early investor in the company, said Mr. Belldegrun. A spokesman for Mr. Milken, who declined to confirm the investment, said the former junk-bond king’s “more than four decades of philanthropic work in medical research and public health has given him a deep understanding of the potential for lifesaving advances.”
Deerfield Management owns about 4% of the shares of bluebird, according to the most recent filings, while Steve Cohen ’s Point72 Asset Management LP owns nearly 2% of the shares. A spokesman for Point72 didn’t comment.
Amazon.com Inc. founder Jeff Bezos and Microsoft Corp. co-founder Paul Allen are investors in Juno, says Robert Nelsen, co-founder of Seattle-based venture-capital firm Arch Venture Partners, which controls stakes worth about $1 billion in nearly a half dozen companies pursuing immunotherapy and other cancer treatments. Arch owns about $470 million in shares of Juno, a company Arch co-founded, as well as $78 million of bluebird.
“I have been creating biotech companies for 28 years and this is the first one where the jaded doctors who have seen everything and have lost hope are shaking their heads in amazement,” said Mr. Nelsen, a managing director at Arch, which manages more than $2 billion.
A spokesman for Mr. Allen confirmed his investment in Juno. A spokesman for Amazon.com declined to comment.
Pension funds and venture-capital funds also are among those riding immunotherapy investments higher. The Alaska Permanent Fund Corp. was an early investor in Juno and controls a nearly 30% stake in the company worth about $1.1 billion. The state investment fund has yet to cash out any shares.
Bristol and others working on immunotherapy drugs, including Merck, Roche Holding AG , AstraZeneca PLC and Novartis AG , are so large the financial impact of their immunotherapy drugs could be diluted by other businesses. That is why investors are bidding up smaller companies.
Not all the immunotherapy news has been upbeat, though: Dendreon Corp. , whose prostate cancer vaccine Provenge was hailed as the first immunotherapy at its approval in 2010, foundered amid limited efficacy, marketing gaffes, and better rival medicines. Dendreon is expected to be sold this month under bankruptcy court supervision to Valeant Pharmaceuticals International Inc. for $495 million.
The intense interest in immunotherapy, an idea that dates back to the 19th century, has emerged from a key discovery researcher James Allison made in the mid-1990s.
Dr. Allison, now the head of immunology at MD Anderson Cancer Center in Houston, discovered a way of releasing a natural brake on the immune system. Dr. Allison’s work paved the way for the development of Bristol-Myers’s Yervoy drug, which was approved in 2011 and was the first drug ever shown to improve survival in patients with advanced melanoma.
“Our understanding of the immune system, and how it interacts with cancer, has grown dramatically,” says Dr. Jill O’Donnell-Tormey, chief executive and director of scientific affairs at the Cancer Research Institute, which funds immunotherapy research.
Write to Gregory Zuckerman at gregory.zuckerman@wsj.com and Ron Winslow at ron.winslow@wsj.com
