Al Malkinson the Scientist: Eulogy by Dr. Lori Dwyer-Nield
Aug16

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

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.   Al the Scientist by Lori Dwyer-Nield as presented 11 August 2012 at Community United Church, Boulder, CO It’s an honor to speak about Al the scientist.  Al was my mentor and friend for 21 years, and in that time I learned that ‘Al the scientist’ was a complex character.  The more I think about it, though, I realize that Al the scientist was the same person as Al the family man and Al the writer.  We called Al our lab Dad.  I remember when I first interviewed for a post-doc position in Al’s lab, he had me meet with his lab first, and then with him.  That was quintessential Al.  His approach to lab management was egalitarian.  We all had to approve new lab members before he would let them join.  He saw his lab personnel as colleagues and friends, not employees.    In his eyes, the high school student or dishwasher was just likely to come up with the next great idea as anyone else.  And if someone contributed to a study, they got their name on the paper. He cared about each individual.  It didn’t matter if you needed to talk to him about a personal problem or an irksome experiment.  He did his best to help.  He was happy when one of his lab personnel got married, but he loved the babies.  Many mentors discourage having a family, but Al knew that family was important.  He also felt that we needed to have interests outside the lab, and even told one young...

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Antibody-drug conjugates: not exactly “smart bombs” for cancer
Jun22

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

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. The study population was 991 breast cancer patients whose disease was previously treated with plain old trastuzumab and a taxane (such as paclitaxel or docetaxel). In this, the EMILIA study, patients were randomized to receive T-DM1 or a combination of capecitabine (Xeloda) and lapatinib (Tykerb). Relative to the latter group, the DM-1-treated patients had a 35 percent increase in “progression-free survival,” the time from treatment to worsening of the disease or death (9.6 months vs. 6.4 months). The T-DM1-treated patients also experienced a reduction in serious adverse effects (40.8 percent vs. 57.0 percent). Large media organizations promoted this drug as a “smart bomb” or “wonder drug.” The truth, as Jarvis reports, is that this promising technology is still in the experimental phase following the 2010 withdrawal of the first FDA-approved ADC, Mylotarg, due to severe liver toxicity and poor treatment response in acute myeloid leukemia (AML). Don’t get me wrong. The ADC field is fascinating and full of promise. But mainstream-media editors who simplify headlines have oversold the findings, potentially misleading patients who might not read all of the study details. Moreover, the T-DM1 findings are in abstract form at this point. The comprehensive article by Lisa Jarvis details some of the technical challenges in creating ADCs but the high promise of these therapies based on the breadth of companies with ADCs currently in development. Go and read. Disclosure: The primary author of the ASCO report, Duke oncologist Dr. Kim Blackwell, is a family friend and colleague. I also had a professional interest in antibody-drug conjugates while working at RTI and was co-author on a paper with investigators from Seattle Genetics in this regard. Reference: Jarvis, Lisa M. Rethinking antibody-drug conjugates. Chemical & Engineering News 90(25): 12-18 (18 June...

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Bad news for Bionovo and herbal drug development
Mar11

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. Some of their early work was with a molecular endocrinology physician-scientist Dale Leitman, then at UCSF. Leitman has a solid track record in the transcriptional regulation of estrogen receptor-beta (ERβ), particularly by natural products such as soy isoflavones. Leitman led the group that reported in 2007 that a 22-herb extract, Bionovo’s MF101 (Menerba), had selective ERβ agonist activity with the potential for treating menopausal symptoms without increased risk of breast cancer. This extract advanced to Phase III trials last October. Even more interesting to me was Bionovo’s extract of Scutellaria barbata (BZL101, Bezielle). Given the recent enthusiasm in searching for drugs that targeted the aerobic glycolysis phenotype of many cancers, BZL101 was exciting because it had these effects in cell culture and was formulated into an oral preparation with good bioavailability. (I should make the disclaimer here that my wife, a former Duke University breast oncologist, enrolled patients in a Phase I trial of BZL101 and was co-author of a 2008 ASCO abstract on the results. However, she received no personal compensation for this work and we have never...

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FDA Withdraws Avastin Approval for Breast Cancer
Nov18

FDA Withdraws Avastin Approval for Breast Cancer

  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. Of course, there are cases of individual patients who have benefited from Avastin and many questions remain for them. In the 69-page ruling made available today (PDF), Dr. Hamburg includes a well-articulated Q&A for patients and their caregivers. I doubt seriously that the full text of this section will be published in the mainstream media, although Pollack does provide the hyperlink. I found this quite valuable as someone who cares about family and friends with breast cancer. But the text also provides an espeically close look at the rationale behind the US drug approval process. As this rich information is buried in a 69-page federal document, I wanted to provide this text here for ease of reading by those concerned about this ruling. This following statement is from US FDA Commissioner Dr. Margaret Hamburg. The full text is in the public domain and can be accessed here.   I. AN EXPLANATION FOR PATIENTS AND THOSE WHO SUPPORT THEM This document, which lays out the basis for my decision, has several purposes. It is an explanation, for physicians, scientists, patients and the public in general, of the data available on the metastatic breast cancer indication for Avastin and of FDA’s evaluation of those data. It also describes how FDA has applied the law and its regulations in making the decision to withdraw the approval for that indication. I know I speak on behalf of the many physicians that have been involved with this issue here at the Food and Drug Administration and elsewhere in saying that we encourage patients and those who support them, to ask hard questions and to demand explanations concerning the drugs that are recommended to...

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Mike Kastan to lead Duke Cancer Institute
May16

Mike Kastan to lead Duke Cancer Institute

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. Central to the new organization is the anticipated February, 2012 completion of a new, seven story cancer research and treatment tower at the center of the medical campus. As an investigator, Kastan is perhaps best known for his groundbreaking work in the early 1990s that revealed the tumor suppressor protein, p53 (TP53), in the DNA damage and cell cycle arrest response. These studies not only revealed how loss of p53 could contribute to tumorigenesis but also established mutant p53 as an anticancer drug target. Of pride and relevance to readers of this blog is that Kastan, a high ranking research and patient care administrator, was originally trained as a chemist. From the Duke press release: Kastan grew up in Charlotte, N.C., and earned a degree in chemistry in 1977 as a Morehead Scholar at the University of North Carolina at Chapel Hill. He won the prestigious Venable Medal in UNC’s Department of Chemistry in 1977. He then graduated from Washington University School of Medicine in St. Louis, Mo., and trained in pediatrics at The Johns Hopkins Hospital in Baltimore, Md. He remained at Johns Hopkins until 1998, when he joined St. Jude as chairman of the department of hematology/oncology. Yes, a CHEMIST! And from a great chemistry department to boot! I had the pleasure of working with Mike for a few years in the 1990s at the Molecular Biology in Clinical Oncology Workshop of the American Association for Cancer Research. I couldn’t be more excited about him joining the Research Triangle scientific community. Most noteworthy to me is that the press release contains a range of enthusiastic comments about Kastan from both within and outside of Duke. The excitement, I think,...

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Winners in The Henrietta Lacks Foundation design contest
Apr08

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. The first entry ended up being among the top two: this from Holly Gaskamp, an Austin, Texas-based designer who freelances professionally as HollyCopter Design and works a day job as a designer for a local television station. Alerted by her boyfriend, a chemistry graduate student at Southern Methodist University and loyal reader of our blog, Holly came up with several designs the very first day of the call for entries. “I don’t know anything about chemistry really and I have no idea what HeLa immunofluorescence is but I thought I could try anyways!,” said Holly. Holly came up with several designs in response to our request for 1) “I [heart] HeLa” and “Thank You HeLa” buttons and 2) a HeLa T-shirt that made use of the HeLa immunofluorescence image made by Dr. Omar Quintero and used in The Immortal Life of Henrietta Lacks. The first round of designs were fabulous but ScienceOnline2011 organizing goddess, Karyn Traphagen, reminded me that regardless of who does the design, the fluorescence micrograph might be difficult for a T-shirt maker to print digitally. (Hence why I put out a call for people who know more about this than I.) So, Holly came back with a vectorized, four-color design based on the four fluorophores that Omar used on his HeLa cells. The result is being held above by yours truly at the exhibitor booth and shown here in greater detail. The reverse of the shirt then reads simply henriettalacksfoundation.org. We (Rebecca Skloot, her assistant Renee Coale, my wife, and I) liked this main image so much that we decided to also use it for one of the four sets of buttons. Holly also fashioned a heart using the same...

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