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Al Malkinson the Scientist: Eulogy by Dr. Lori Dwyer-Nield

Lori Dwyer-Nield, PhD, Associate Research Professor, School of Pharmacy, University of Colorado Denver’s Anschutz Medical Campus; Investigator, Eastern Colorado Veterans Hospital

In this second part of my remembrance of lung cancer biochemical pharmacologist, Colorado’s Dr. Al Malkinson, I’d like to share with readers some recollections by Lori Dwyer-Nield, PhD. I’ve known Lori since my appointment to Colorado’s faculty in 1992 when she had already been a postdoctoral fellow of Al’s. Dr. Dwyer-Nield continued on as research faculty at the CU School of Pharmacy and co-authored over 40 publications with Al.

At Al’s memorial service last Saturday in Boulder, Lori was asked by Al’s wife, Lynn, to eulogize Al on behalf of all his scientific colleagues. Her thoughts were so warmly received that I wanted to share them more widely, especially with members of the scientific community who knew Al but were unable to attend the memorial. Moreover, I had reflected in my previous post how supportive Al was of his women trainees in balancing career and family. This eulogy provides a glimpse into this philosophy of Al’s directly from someone who lived it for over 20 years.

My tremendous thanks go out to Lori for agreeing to share with us this text of her eulogy.

 


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Antibody-drug conjugates: not exactly “smart bombs” for cancer

Antibody-drug conjugates are the cover story in the 18 June 2012 issue of C&EN. Illustration credit: ImmunoGen.


I only have a quick post today because I really want you to spend your reading energy on a superb C&EN cover story by my colleague here, Lisa M. Jarvis.

The media frenzy that normally follows the American Society of Clinical Oncology (ASCO) meeting each June focused this year on cancer cell-directed antibodies conjugated to highly-cytotoxic compounds. The most ballyhooed of these is T-DM1, the anti-HER2 trastuzumab antibody (Herceptin) covalently linked to the microtubule-inhibiting maytansine analog, DM1 (meeting abstract, Genentech press release). When the conjugate is internalized by breast cancer cells overexpressing the HER2 protein, the highly-toxic DM1 drug is released intracellularly.

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Bad news for Bionovo and herbal drug development

A pharmacognosy colleague contacted me on Friday morning with word that the botanical drug development company Bionovo was closing its chemistry group.

Well, the news is actually worse as judging from this 8 pm Friday press release:

Bionovo, Inc. (OTC Link Platform: BNVI.PK) today announced that it will need to obtain substantial additional funding to achieve its objectives of internally developing drugs. The Company reduced its workforce by over 90%. The remaining management of the Company will receive reduced cash compensation until either adequate financing can be obtained or the Company is sold.  The Company can not make any assurances about either of these events.  As previously announced, management and the board of directors are continuing to explore strategic options for the Company.  Management is currently reviewing the status of the ongoing clinical trial for Menerba.

The Company does not currently have adequate internal liquidity to meet its cash needs.  If sufficient additional funds are not received in the near term, the Company may not be able to execute its business plan and may need to further curtail or cease operations.

Bionovo has been the rare superb example of a company that’s been trying to develop FDA-approvable drugs based on Chinese traditional medicine. Led by Isaac Cohen, a UCSF guest scientist and Doctoral of Oriental Medicine, and chief medical officer, Mary Tagliaferri, Bionovo took a hard, science-based approach to identifying herbal extracts for cancer and women’s health issues. Cohen and colleagues at UCSF and elsewhere examined Chinese herbal medicines for their biochemical and cellular effects based upon their traditional use.

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FDA Withdraws Avastin Approval for Breast Cancer

Schematic of humanized anti-VEGF antibodies. Credit: Steinbrook R. NEJM 2006; 355:1409-1412. Click on illustration for the source article.


 
As reported around the wires today, US FDA Commissioner Dr. Margaret A. Hamburg formally revoked the accelerated approval of the antiangiogenic drug Avastin (bevacizumab) for breast cancer treatment. Avastin is a humanized mouse antibody that binds and inactivates the vascular endothelial growth factor VEGF-A, a mediator of blood vessel growth. Andrew Pollack at The New York Times does a nice job condensing this episode for us.

The highlights are that Avastin was approved based on the surrogate endpoint of progression-free survival in metastatic breast cancer, meaning that it appeared to increase the time from treatment to return of the growth of cancer metastases. However, the true endpoint is long-term patient survival. There, subsequent studies showed that Avastin had no benefit.

Moreover, Avastin also use appears to increase the risk of hemorrhage and bowel perforation. These are potentially life-threatening side effects and are considered too great of a risk when no statistical benefit of survival or quality of life are apparent.

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Mike Kastan to lead Duke Cancer Institute

Michael Kastan, MD, PhD, will lead the newly-reorganized Duke Cancer Institute. Credit: DCI

The NCI Comprehensive Cancer Center at Duke University has just announced that Michael Kastan, MD, PhD, will become its new executive director. Kastan currently serves as director of the cancer center at St. Jude Children’s Hospital in Memphis, a position he has held since 2004. A well-respected physician-scientist, Kastan oversaw St. Jude becoming the first pediatric cancer hospital to receive NCI comprehensive status.

A start date for Dr. Kastan was not apparent from the press release.

Kastan’s move to Duke comes at a critical juncture for the cancer treatment and education enterprise at the University. The Duke Cancer Institute is the entity resulting from a reorganization of the Duke Comprehensive Cancer Center in November 2010:

By uniting hundreds of cancer physicians, researchers, educators, and staff across the medical center, medical school, and health system under a shared administrative structure, the DCI will offer unprecedented opportunities for teamwork among the scientists in our labs and caregivers in our hospitals and clinics.

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Winners in The Henrietta Lacks Foundation design contest

First things first: Congratulations to Holly Gaskamp (hollycopter) and Michael Lombardi (Amoeba Mike)!

Let me explain. The last two weeks have been a whirlwind while planning for the 102nd Annual Meeting of the American Association for Cancer Research (AACR) held April 2-6 in Orlando, Florida. Having been invited by author Rebecca Skloot to serve on the board of The Henrietta Lacks Foundation, we used our recently-awarded 501(c)(3) status (non-profit charity) to host an exhibitor’s booth at the meeting.

Given the very short timeline between this IRS ruling and the meeting, I turned to you – dear readers – for graphic design expertise to fashion buttons and T-shirts to award at the meeting booth to promote the mission of the Foundation: “Helping those who’ve unknowingly made important contributions to science.”

Well, we were fortunate to receive a wave of entries into our contest and two designers were selected to imprint their designs on official HeLa Foundation paraphernalia.

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HeLa T-shirt and button design contest

Wanna put your mad Photoshop skillz to a good non-profit cause?

Rebecca Skloot, author of The Immortal Life of Henrietta Lacks, (and I) need your help for scientist give-away items to support The Henrietta Lacks Foundation. Scroll down to the end of the post for information on the Foundation’s mission or just click here.

I’ll be at the 102nd Annual Meeting of the American Association for Cancer Research in Orlando during first week of April and will be manning a booth to promote the Foundation to raise awareness about our mission and, hopefully, cultivate philanthropy among individuals and companies who may care to support the cause (Disclosure: I am a non-compensated member of the Foundation’s Board of Directors).

We want to offer two types of promotional items that are beyond my graphic design skills:

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Molecular Target for Thunder God Vine

This post appeared originally last Friday for my monthly gig at Science-Based Medicine.

ResearchBlogging.orgThunder god vine may not be a useful herbal medicine but the compounds isolated from it are fascinating – if not as medicines, then most certainly as laboratory tools. Nature Chemical Biology recently published an article where a research team from Johns Hopkins, the University of Colorado at Boulder, and Drew University in New Jersey, has determined the molecular mechanism of action of triptolide, an unusual triepoxide compound from the plant.

Tripterygium wilfordii Hook F, or thunder god vine, is known as lei gong teng in Chinese traditional medicine and has a history of use as an anti-inflammatory herb. As with many traditional medicines, usage patterns do not necessarily indicate scientific validity. In fact, a Cochrane review published just last month on herbal therapies for rheumatoid arthritis indicated that the efficacy of thunder god vine was mixed. More concerning is that the herb had significant adverse effects in some trials, from hair loss to one case of aplastic anemia.

Nevertheless, the herb’s components have been studied since the 1970s for since they also appears to kill tumor cells in culture with nanomolar potency and have immunosuppresant activity in animal models. The group of the late natural products chemist at the University of Virginia, S. Morris Kupchan, first identified the unusual structures of triptolide and tripdiolide from Tripterygium wilfordii as described in this 1972 paper from the Journal of the American Chemical Society. Cytotoxic activity toward tumor cells in culture was used to guide the chemical fractionation of extracts. The unusual presence of three consecutive epoxides in the structures of both compounds led Kupchan to hypothesize later in Science that they target leukemia cells by covalent binding to cellular targets involved in cellular growth.

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The Man Who Gave Us Epo

Professor Eugene Goldwasser (center) and future Nobel laureate Prof Harald zur Hausen (left) with King Bhumibol Adulyadej of Thailand (right) after receiving the 2005 Prince Mahidol Award. Source: Prince Mahidol Award Foundation.

I learned over the weekend via this tweet from Serena Stockwell at Oncology Times that Eugene Goldwasser passed away on Friday at age 88. The biochemist and renal physiologist who spent most of his career at the Argonne National Cancer Hospital and Department of Biochemistry and Molecular Biology at the University of Chicago (web page) demonstrated that a hormone made in the kidney could increase the number of new red blood cells, a major advance in physiology. His laboratory purified the protein hormone, erythropoietin (or Epo), from sheep in 1971 and from humans in 1977.

While a remarkable discovery of its own, Goldwasser’s partnership with then-Applied Molecular Genetics (Amgen today) led to the first- and second-generation recombinant biopharmaceuticals, erythropoietin and darbopoietin, and other versions such the the PEGylated EPO, Mircera. These drugs have transformed the lives of kidney dialysis and cancer patients, raised a furor in competitive sports – cycling in particular – and have been central to some of the most robust legal wrangling and medical costs discussions of our generation.

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Arsenic-permissive bacteria – implications for arsenical cancer chemotherapy

Like many of you, I waited this week for details on the NASA press conference and Science paper on a major discovery – painted as an “alien lifeform” by some news outlets. The truth did not live up to the hype but it was an impressive biological finding: a group led by Felisa Wolfe-Simon discovered a bacterium in California’s Mono Lake that could still grow when phosphorous was completely replaced with arsenic. The bacterium, strain GFAJ-1 of the Halomonadaceae family of Gammaproteobacteria, appears to use arsenic in place of phosphorus in molecules where phosphate is used – shown most conclusively here for DNA.

The story is perhaps best told by science writer extraordinaire, Ed Yong, at Not Exactly Rocket Science, and biologist PZ Myers is to be commended for representing us well to our chemistry colleagues by actually breaking out the periodic table in his excellent teaching post.

Addendum (4 Dec, 2:46 pm): An excellent chemistry-flavored post at The Curious Wavefunction also came to my attention – he/she cited this great 1987 Science paper, “Why Nature Chose Phosphates (PDF),” from the late Harvard chemist Frank Westheimer which discusses, among other things, the difficulties in overcoming the lability of arsenate esters in biomolecules.

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