Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Science’

Taxanes are a class of drug that are used in breast, lung and ovarian cancer chemotherapy to disrupt the function of microtubules that are essential to cell division. They include paclitaxel (Taxol®) and docetaxel (Taxotere®).

Paclitaxel is also used to prevent the narrowing (restenosis) that occurs with coronary artery stents that are used to open blocked coronary arteries. Drug coated stents (a.k.a. “drug-eluting stents) reduce scar tissue.

Research published in the February 18, 2011 edition of Science, by Farida Hellal and colleagues has now shown that treatment with paclitaxel reduces the scarring associated with spinal cord injury (SCI) and promotes nerve regeneration.

The paper in Science is well worth reading and takes the reader through a logical thought process as the researchers tested their hypothesis that paclitaxel might stabilize microtubules around the site of SCI.

One of the cellular events that occurs after SCI is the activation of transforming growth factor-ß signaling (TGF-ß).

Increased TGF-ß leads to fibrosis or scarring.  TGF-ß acts on Smad2 to bind to microtubules through kinesin-1.  Hellal and colleagues asked if treatment with paclitaxel would impair Smad-dependent TGF-ß signaling? The answer from their elegant series of experiments is that yes it does.

Not only that, but TGF-ß also regulates the axon growth inhibitor, chondroitin sulfate proteoglycans (CSPGs).  The researchers asked whether pacllitaxel decreased CSPGs after SCI?  They found that cultured meningeal cells and astrocytes treated with 10 nM paclitaxel showed a 35% and 32% decrease of glycosaminoglycan (GAG) levels.

The next logical question is whether the reduction of scar formation by paclitaxel results in any benefits for new nerve formation? The regeneration of dorsal root ganglions (DRG) were evaluated.  In what to me was a finding of great significance, the researchers found (references to figures omitted) that:

“Taxol-treated animals had regenerative fibers growing along the edge of the lesion cavity into the injury site and beyond. The longest axons per animal grew 1199 T 250 mm in the Taxol-treated group versus 176 T 225 mm in the vehicle-treated an- imals (n = 13 animals per group; P = 0.002; two- tailed t-test). The Taxol-treated lesion site thus becomes favorable for regeneration of growth-competent axons.”

The final part of this research asked whether treatment with paclitaxel led to any functional improvement after the test animals received a spinal cord injury? They found that those rats that received paclitaxel after injury, had greater improvement in their locomotor function.   The conclusion being that “Taxol-induced functional recovery correlates with its axon growth–inducing effect.”

The results from any animal study must be viewed with caution, since they don’t necessarily translate to humans.  However, this animal research, if supported by data from human clinical trials, suggests that treatment with taxanes may be of benefit to those with spinal cord injuries.

Given the debilitating effect of any spinal cord injury, this is an important finding.


ResearchBlogging.orgHellal, F., Hurtado, A., Ruschel, J., Flynn, K., Laskowski, C., Umlauf, M., Kapitein, L., Strikis, D., Lemmon, V., Bixby, J., Hoogenraad, C., & Bradke, F. (2011). Microtubule Stabilization Reduces Scarring and Causes Axon Regeneration After Spinal Cord Injury Science, 331 (6019), 928-931 DOI: 10.1126/science.1201148

That is the interesting question that struck me after reading Sam Kean’s informative article in the February 4 edition of Science.  Ten years on from the sequencing of the Human Genome, the patenting of human genetic information presents unique challenges at the interface of science, law and innovation.

Researchers have obtained patents for isolating different sections of DNA that occur naturally in our bodies.  Whether this should be permitted is still open to debate. Currently, diagnostic companies who want to launch a new cancer test face the challenge that patents now cover many genes.

The Science article cites start-up Foundation Medicine in Cambridge, MA who estimated the cost of investigating possible patent infringement for a new diagnostic test at $35M, a cost that exceeded the company’s $25M of VC funding.

Add in the costs of any royalties or licensing fees and the issue of prior patents is now a nightmare for any diagnostics company.  It is simply not practical to license every gene that may be implicated in a multifactorial disease such as diabetes.  Pre-existing patents have become a barrier to market entry.

As the Science article reports, gene patents cover not only very small snips of DNA, as short as 15 nucleotides, but can prohibit the sequencing of associated DNA. Companies such as 23andMe that sequence an individual’s genome to test for the presence of certain genes may be violating patent rights of others.

What’s more so called “method” patents cover the linking of a gene sequence with a specific medical condition.

As advances in personalized medicine continue, there is a need to balance the competing interests of protecting scientific discovery and rewarding innovation, while at the same time allowing access to human genetic information that many think should be “free to all men and reserved exclusively to none.” Quotation from Bilski v. Kappos, 130 S.Ct. 3218, 3225 (2010)

A law suit currently on appeal to the US Court of Appeals for the Federal Circuit may lead to a change in the current practices of the US Patent & Trademark Office.  The American Association of Pathologists and others have challenged several patents relating to the breast cancer genes BRCA1 and BRAC2 held by Myriad Genetics and the University of Utah Research Foundation.

BRCA1 and BRCA2 genes are associated with an increased risk of breast and ovarian cancer.  The US district court for the Southern District of New York in a surprise decision by Judge Robert Sweet, invalidated Myriad’s patents.  The New York Times article about the case has a link to the Judge’s 156 page opinion.  The decision that isolated but otherwise unaltered DNA should not be patentable is now being appealed by Myriad.

In their legal brief, arguing for the decision to be upheld, the United States Government states:

“The fact that a particular segment of the human genome codes for the BRCA1 protein in a human cell, for example, rather than for adrenaline or insulin or nothing at all, is not within the power of science to alter. Such basic natural relationships may not be the subject of a patent.”

If the District Court’s decision is upheld on appeal, it would represent a fundamental policy shift on what patents can be obtained for human genetic information. Such a decision would prevent Myriad from charging royalties and exclusivity for the genetic testing of BRCA1 and potentially invalidate similar types of patents. Depending on your point of view this will either harm the biotechnology industry or increase the market opportunities.

Given the stakes involved, it is likely the Myriad case will end up being considered by the United States Supreme Court, and what they may decide is anyone’s guess.

To read more in-depth analysis about the Myriad case and the legal issues involved with the patenting of genomic information, I strongly recommend the “Genomics Law Report”, a blog written by Dan Vorhaus and others.

Ten years after the human genome was sequenced we are still working out the intellectual property rights. The question as to whether companies should be allowed to patent unaltered human genes is one that will be answered in the not too distant future.

I recently attended the annual meeting of the American Society of Hematology (ASH) in Orlando so thought I would share my general impressions (in no particular order):

Convention Center Food was Poor:

The food at the Orange County Convention Center reminded me of an airport – desperate choices, poor quality and overpriced.  As for no Starbucks or decent coffee shop, civilization has yet to reach Orlando! The Peabody hotel across the road had coffee shops that offered a $3 single espresso shot, but they ran out of pods on the Monday morning – faced with the overwhelming demand that seems to have not been anticipated!  Memo to Starbucks – look into a convention center franchise.

Cramming all the science in one day doesn’t work:

People go to a meeting such as ASH for many reasons – networking, business development, education, investigator meetings, but in the end, it is a scientific meeting.  The meeting ran from Saturday to Tuesday, yet nearly all the oral scientific program (biology and therapy) was crammed into one day of simultaneous sessions on the Monday – tough if you wanted to cover a product or pathway that targeted multiple therapeutic areas, many of which ran at the same time.

The Poster hall was like a graveyard:

You can tell I didn’t think this was a great meeting. Every time I went into the aircraft like hangar where the posters were housed, I ended up chilled to the bone. It certainly didn’t encourage spending much time there, and I was disappointed that a surprisingly high number of presenters did not attend the poster presentation receptions, when they were supposed to be available to answer questions.  Nobody seemed to check if anybody showed up, to me the whole point of a poster is being able to discuss it.

Why not publish the slides from the oral science presentations?

ASH, unlike ASCO does not make the slides of oral scientific presentations available online, so if you didn’t make notes, or break the rules (and risk being ejected) by taking an illegal picture on your phone or camera, then you missed it.  Abstracts are often submitted months in advance before the final data is analyzed, so by not making the slides available after the meeting, science to me is being hampered especially given the overlap of sessions on the Monday.  If an abstract is presented and published, the scientific information should be available to be shared. Isn’t that what science is about?  ASCO have it right, their virtual meeting program is outstanding.

Hospitality lives on – but only if you are an international doctor:

US doctors attending their annual meeting, are warned not to accept a free cup of coffee at an exhibitor booth if their state or employer prohibits the acceptance of such “gifts”, while foreign physician attendees are wined and dined.  You see signs for hospitality centers for European doctors or desks in hotels for company sponsored groups of foreign doctors – hard to believe there’s ethically not something wrong with these double standards.

A lack of quality educational materials:

While the free pen and notepad have long since gone the way of the dinosaur, this year there was noticeably fewer educational material to take away.  The debate as to whether doctors should pay for their own CME continues, but I do think many in the industry miss the opportunity by not providing educational material on the science, pathways and mechanism of action of new products.

The “Super Friday” is still alive:

Multiple industry sponsored satellite symposia (AKA “Super Friday” sessions) took place before ASH, with several at the Peabody Hotel. I have to say the food at the one I attended on personalized medicine was excellent, one of my best meals in Orlando.  They are not cheap to run: not only do 800-1000 people get fed, but a hotel room with audio-visual equipment has to be hired, a panel of experts are paid to talk about a topic, and many of the attendees come away with a glossy brochure.  Could this money be better spent elsewhere?  ASH has a large education component to it, and it was interesting to note that what the ASH education program committee chose as important topics to talk about and what the industry chose, were pretty different.  That is perhaps not surprising – after all if you choose the topic of the satellite symposia and it’s of relevance to your product, indirectly you are trying to influence prescribing behavior, otherwise why else would you fund it?  There is no such thing as a free lunch or dinner.

Multiple Myeloma was a hot topic:

There was a lot of interest in clinical trial results in MM.  The use of a maintenance therapy, and attempt to turn this into a chronic disease was a widely discussed topic, however many old drugs such as thalidomide have nasty side effect profiles such as peripheral neuropathy, while newer drugs such as lenalidomide are expensive but appear to only incrementally increase survival.  Results from multiple combinations of drugs and induction therapies were presented, I was left with the impression that although there is progress, there is still no major breakthrough in this disease area.

Nobody wants to talk about cost effectiveness:

The 800 lb gorilla in the room for hematology/oncology is the comparative effectiveness of one treatment versus another i.e. it’s cost/benefit, yet nobody wants to talk about it.  Take for example the treatment of CML, should you treat with imatinib (Gleevec) which has outstanding long-term survival data over several years thanks to the IRIS trial, or use a second-generation tyrosine kinase inhibitor (TKI) such as dasatinib or nilotinib that is around twice the price, more potent and slightly more effective but obviously we don’t yet know if it improves 5 or 10 year survival yet over imatinib.  Nobody wanted to talk about price – physicians currently live in an ivory tower.

If you are interested in information on what the hot scientific news was at ASH, then I encourage you to look at the excellent posts (here & here) published by my colleague on Pharma Strategy Blog.

Uveal melanoma is a common cancer of the eye that involves the iris, ciliary body and choroid.  It is a disease that hits 2000 people per year in the United States and is common in those over 50.  Standard treatment involves removal of the eye or radiotherapy. There is an unmet need for systemic drug therapy.

Mutations in the BRAF gene (a member of the Raf family that encodes a serine/threonine protein kinase) have been found in many skin melanomas.  In 80% of the cases, a single point mutation in exon 15 (T1799A) has been shown to occur.  Some new agents in development such as PLX4032, ipilumumab, GSK2118436 have shown promise in advanced skin melanoma, but research suggests that BRAF may not be the key to Uveal melanoma.

Henriquez et al, in a paper published in Investigative Ophthalmology & Visual Science showed that the T1799A BRAF mutation was only present in 9 of 19 iris melanoma tissue samples, but only in one case of uveal melanoma, suggesting differences in the genetic and clinical differences between the two.

Recently, two papers have been published that provide new insight into this intraocular cancer. In the December 2, 2010 issue of the New England Journal of Medicine, Van Raamsdonk et al, found mutations of either the GNAQ or GNA11 gene to be present in 83% of uveal melanomas that were sequenced (n=713).

Harbour et al, in the December 3, 2010 issue of Science reported findings of a frequent mutation of BAP1 in metastasizing uveal melanomas. They found that in 26 of 31 (84%) of uveal melanoma tumors they examined, there was a mutation of BAP1, the gene encoding BRCA1 associated protein 1 (BAP1) on chromose 3p21.1. The results published in Science, “implicate loss of BAP1 in uveal melanoma metastasis and suggest that BAP1 pathway may be a valuable therapeutic target.”

The data suggests that there may be multiple pathways involved in uveal melanoma.  It is promising to see translational medicine in action, with scientists seeking to understand the molecular basis of a disease so that targeted therapies can be developed.  Uveal melanoma only strikes a relatively small number of patients, but if a highly effective drug can be developed, this could be a market opportunity worth pursuing.

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