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

Posts from the ‘Translational Medicine’ category

AACR 2013 DMUC5754A is a novel agent for Ovarian Cancer

The cherry blossoms are finally blooming in Washington DC for the 2013 annual meeting of the American Association for Cancer Research (AACR).

With AACR in DC this year, the following traditional Japanese haiku published on the National Park Service website struck me as appropriate for cancer researchers and survivors to reflect on:

Yo no naka wa, Mikka minu ma ni, Sakura kana

“Life is short, like the three day glory of the cherry blossoms.”

Yesterday at AACR was predominantly an educational day, but several studies were highlighted to the assembled media.  One of the late-breaking clinical trials that caught my attention was the preliminary phase 1 data on Genentech’s novel new agent DMUC5754A.

Joyce Liu MD MPH. Photo: Dana-Farber Cancer Institute

Joyce Liu MD MPH

LB-290 Targeting MUC16 with the Antibody-Drug Conjugate DMUC5754A in patients with platinum-resistant ovarian cancer.  This data will be presented by Joyce Liu, MD, MPH from Dana-Farber Cancer Institute in the Clinical Trials Symposium on Tuesday, Apr 9 at 4.00 pm.

Dana-Farber issued a press release yesterday  – here’s the link. The picture of Dr Liu is from her Dana-Farber profile.

Ovarian cancer causes more deaths in women than any other cancer of the reproductive organs, with an estimated 20,000 women diagnosed with this cancer each year.  The majority of women are treated with traditional platinum based chemotherapies, and most of these relapse and develop drug-resistant disease.  This makes the development a new novel agent such as DMUC5754A that will treat platinum-resistant ovarian cancer a major potential breakthrough.

In an AACR media release, Dr Liu commented on how the drug works:

“This drug consists of an antibody and a potent toxin joined by a cleavable linker. The antibody identifies a protein, MUC16, which is highly expressed in ovarian cancers, and targets the toxin to kill the cancer cells.”

Liu went on to note that, “Unlike other cancer treatments, the antibody-drug conjugate releases the toxin with relative selectivity to the MUC16-positive cancer cells.  This allows delivery of drugs that would otherwise be too toxic for treatment.”

According to Liu, “If the activity of this drug is confirmed in additional trials, this will represent a novel type of therapy for ovarian cancer, with effectiveness in platinum-resistant ovarian cancer, which is the hardest type of ovarian cancer to treat.”

Genentech are particularly good at sharing early data at AACR, and based on the promising responses in MUC16 IHC 2/3+ patients, this new ADC compound is likely to progress to phase 2 – a compound to watch out for in the future.

ASH 2012: CTL019 chimeric antigen receptor technology emerging as a new leukemia treatment

For many attendees, the most exciting news at the 2012 annual meeting of the American Society of Hematology (ASH) held last December in Atlanta was the prospect of personalized T cell therapy for the treatment of patients with B cell cancers such as chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).

The potential of this new treatment option was recognized at ASH 2012 by the award to Dr Bruce R. Blazar, MD and Carl H. June, MD of the Ernest Beutler Lecture and Prize for research that generated major translational advances in T-Cell Infusions.

ASH 2012: Carl June, MD receives Ernest Beutler Prize

ASH 2012: Carl June, MD receives Ernest Beutler Prize

Dr June, in his accompanying lecture discussed preliminary data for the trial of CTL019 (formerly CART-19), a novel chimeric antigen receptor-transduced T cell therapy against CD19. Subscribers to premium content can login to read more below:

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In the 12 patients (10 adults CLL and 2 children with ALL) who have received CTL019, the responses have been extremely promising with a clinical response (CR+PR) seen in 9 out of the 12.

There have already been several reports in the media about this trial with many news outlets reporting that one of the children with ALL had been “cured.” That this treatment has tremendous potential is undisputed, but in my view it is a case of “hype over hope” at this stage to say that anyone has been cured in the absence of long-term follow up over at least five years.

In August 2012, Novartis announced they had formed an alliance with the University of Pennsylvania and had obtained a worldwide license to commercialize CART-19 (now CTL019). In December 2012, Novartis purchased a NJ manufacturing facility from Dendreon for $43M that will used for the production of personalized immunotherapy.

Novartis, through their recent acquisition of the Dendreon facility in NJ, are fortunate to gain access to the technology, state-of-the-art tracking system that matches the product to each patient, as well as the Good Manufacturing Practices (GMP) that were pioneered in the production of sipuleucel-T (Provenge).

In the immediate future, Novartis and U Penn have the challenge of showing that the dramatic results seen in some of the initial patients are reproducible in a larger trial and also at institutions other than Penn.

ASH 2012 Carl June Ernest Beutler Prize LectureIn his ASH lecture, Dr June noted that there are side effects and toxicities associated with CTL019 including tumor lysis syndrome (TLS), and Cytokine Release Syndrome (CRS) was seen in all patients.

This suggests it is unlikely this therapy will be used outside of the hospital setting.  In the United States, I would not be surprised to see it only used at hematology transplant centers, where there is the necessary expertise to deal with both the process and any complications that arise. Novartis may end up with a high priced therapy targeted at a small niche market.  It will be interesting to see the commercial strategy that Novartis decide to adopt.

I expect we will hear a lot more about chimeric antigen receptor technology in 2013. Personalized immunotherapy is a complex topic and one that will require significant investment in medical education by Novartis if a broader audience is the intended target. Dendreon failed miserably at launch in explaining how sipuleucel-T (Provenge) worked and did not convince large numbers of medical oncologists that their immunotherapy worked.  Even to this day, there remains considerable sceptism amongst that physician segment.

If you would like to know more about the science behind CAR therapy and it’s potential in hematology, Sally Church, PhD (who co-launched Gleevec in the US while at Novartis Oncology) will be offering insights in a monthly newsletter to be launched soon. Check out Pharma Strategy Blog for more information.

 

ASH 2012: ABT-199 shows promise in CLL and MCL

The “Hallmarks of Cancer” paper by Douglas Hanahan and Robert Weinberg is a classic, and a must read (allow plenty of time) for anyone interested in cancer drug development.

The original 2000 paper, updated in 2011, identified six hallmarks of cancer, “distinctive and complementary capabilities that enable tumour growth and metastatic dissemination:”

  • Sustaining Proliferative Signaling
  • Evading Growth Suppressors
  • Activating Invasion and Metastasis
  • Enabling Replicative Immortality
  • Inducing Angiogenesis
  • Resisting Cell Death

Apoptosis or programmed cell death according to Hanahan and Weinberg is “a natural barrier to cancer development.” One of the ways cancer cells survive is by resisting cell death and disrupting the apoptosis signaling pathway; in other words the normal signals that trigger cell death don’t get through.

Researchers have shown that apoptosis is controlled at the cellular level, in the mitochondrion, by the Bcl-2 family of regulatory proteins (BCL-2, BCL-XL). Targeting BCL-2 (a protein that prevents apoptosis) could induce cell death and be a potentially successful anti-cancer strategy.

The result of our increased understanding of cancer biology has been the development of novel targeted drugs such as ABT-199, a potent and selective BCL-2 inhibitor. This is in early clinical development by AbbVie ($ABBV), a new biopharmaceutical company spun off from Abbott Laboratores ($ABT) last week.

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I previously wrote about the potential for ABT-199 in Chronic Lymphocytic Leukemia (CLL) following Steven Elmore’s presentation at the April, 2012 annual meeting of American Association for Cancer Research (AACR).

The data presented at AACR has now been published in Nature Medicine, online ahead of print (AOP) on 6 January 2013: “ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.”

Andrew Souers and colleagues from AbbVie and other institutions discuss how they re-engineered the since-discontinued navitoclax (ABT-263) to create a different and less toxic BCL-2 inhibitor. This new compound, unlike navitoclax, does not cause the thrombocytopenia associated with BCL-2-like1 (BCL-XL) inhibition.  It’s a compelling story of science-based cancer drug development.

ASH 2012 Annual Meeting BannerAt the December 2012 annual meeting of the American Society of Hematology (ASH) in Atlanta interim data was available from the phase 1 clinical trial of ABT-199 in Non-Hodgkin Lymphoma (abstract #304).

Matthew S. Davids, MD, Instructor in Medicine at Harvard Medical School & attending physician at the Dana Farber Cancer Institute, presented the results from the first-in-human phase 1, open-label, dose escalation, multicenter international trial in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL).

Of the 30 NHL patients enrolled, Dr Davids told the audience that 20 remained active, with a median time on study of 80 days (range 7 to 413).

ABT-199 particularly active in CLL & MCL

In 7 patients who had mantle cell lymphoma (MCL) in the 30 subject NHL trial, all seven (100%) obtained a partial remission.  A 72 year old man with stage IV MCL obtained complete clinical resolution of auxiliary node clinically and 2 x 1 cm neck nodes by day 8.

ABT-199 is also active in CLL. Dr Davids briefly shared data previously presented at the 2012 Congress of the European Hematology Association (EHA) last year.  The waterfall plot was quite impressive, unfortunately I could not obtain permission to share an iPhone photograph here.  However, by my eye, the plot appeared to show that 30 of the 37 evaluable patients had a greater than 50% reduction in nodal size!

Dr Davids shared by email some additional commentary on the potential of ABT-199 in CLL:

“ABT-199 appears to be very active in patients with relapsed refractory CLL irrespective of high risk features such as del(17p).

Given its distinct mechanism of action from the BCR pathway antagonists, it has the potential to become an important additional treatment option in the armamentarium of CLL therapies.

Whether ABT-199 will be most useful as a signal agent, in combination with chemotherapy, or in combination with other novel agents will be an important question moving forward.”

ABT-199 has an acceptable safety profile

ABT-199 related grade 3 / 4 neutropenia was experienced in 3 of the 30 NHL phase 1 trial participants (10%).  Dr Davids noted there were:

  • No discontinuations due to adverse events
  • No dose limiting toxicities observed in NHL patients
  • No evidence of dose-dependent thrombocytopenia

He concluded that ABT-199 had an acceptable safety profile and further research is ongoing in NHL, both as a single agent and in combination with bendamustine/rituximab.  The lack of severe thrombocytopenia is a definite improvement on its predecessor navitoclax.

Overall, ABT-199 is an exciting new agent in development with potential as a new treatment option for CLL & MCL.  I look forward to hearing more about it at future scientific meetings.

Improving Clinical Trials through the use of Biomarkers

What is a Biomarker?

According to the Biomarkers Definitions Working Group, a biomarker is:

“a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”

An example of a common biomarker is blood pressure. High blood pressure is a surrogate for cardiovascular disease and risk of stroke.

Why are biomarkers important? Subscribers can login to read more below.

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Why are Biomarkers important?

Biomarkers can be used for diagnosis and for monitoring the safety and effectiveness of treatments. They are increasingly becoming important in the selection of patients for clinical trials, and as potential surrogates for clinical endpoints that may take a long time to occur e.g. measuring how long someone will live in a cancer trial (overall survival).

Examples of the use of biomarkers include:

  • Diagnosis: high blood pressure is used as a biomarker for cardiovascular disease and risk of stroke.
  • Treatment Selection: CSF biomarkers that correlate with neurodegenerative diseases may help select the most appropriate treatment
  • Drug Effectiveness: biomarkers can be used to monitor treatment or drug effectiveness e.g. use of cholesterol levels as a measure of cardiovascular disease
  • Surrogate Clinical Endpoint: a biomarker based on scientific evidence that predicts or correlates with clinical benefit could be used as a surrogate for a clinical endpoint that may take a while to detect e.g. how long a patient lives or survives, and in the process speed up drug development. Recent prostate cancer trials sought to show that circulating tumor cell (CTC) counts correlated with the survival benefits seen. However, validation of a biomarker needs to take place before regulatory agencies will accept it as a surrogate endpoint in clinical trials.

Biomarkers can be divided into those which are prognostic and those that are predictive.

Prognostic Biomarker: a marker that provides information on the likely course of a disease in an untreated individual.

Prognostic biomarkers are used to identify high-risk cancer patients who should, therefore, receive adjuvant therapy.

Predictive Biomarker: a marker that provides information on how likely you are to respond to a particular therapy.

Predictive biomarkers are used to guide treatment choices i.e. selecting the therapy with the highest likelihood of success.

In breast cancer, estrogen and progesterone receptors are biomarkers that predict sensitivity to endocrine therapy, while HER2 levels predict response to Herceptin treatment. In colorectal cancer (CRC) patients, KRAS mutations have been shown to be a biomarker of resistance to EGFR targeting drugs such as cetuximab and panitumumab.

Predictive biomarkers allow expensive new cancer treatments to be given only to those patients who are likely to respond. As we move forward into the era of personalized medicine the aim is to develop more highly predictive biomarkers that will allow better detection, diagnosis and treatment of disease.

In addition, there’s also a need to develop biomarkers that can distinguish between subgroups of patients to separate those who might benefit from a therapy and those who have developed resistance. Biomarkers for resistance to cancer therapy is an increasingly important area of research.

For those readers interested in cancer biomarkers, the joint ASCO-EORTC-NCI “Markers in Cancer” 2012 meeting in Hollywood, FL (near Fort Lauderdale) from October 11-13 has an agenda that holds promise.

Some of the presentations that caught my attention and ones I particularly look forward to watching remotely via the “Virtual Meeting” include:

  • Biomarkers of Resistance to EGFR-Targeted Therapies in Lung Cancer
    Enriqueta Felip, MD, PhD – Vall d’Hebron University Hospital
  • Resistance Mechanisms to BRAF Inhibition in Melanoma
    Jeffrey Sosman, MD – Vanderbilt-Ingram Cancer Center
  • Complexities of Identifying Non-Mutational Biomarkers of Resistance:
    The VEGF Pathway Example
    Michael B. Atkins, MD – Georgetown University
  • Development of Biomarkers for PI3K Pathway Targeting
    Sherene Loi, MD, PhD – Jules Bordet Institute, Brussels
  • Emerging Functional Imaging Biomarkers
    Annick D. Van Den Abbeele, MD – Dana-Farber Cancer Institute

The next post in this mini-series will discuss new research that shows how a panel of 5 CSF biomarkers can be used to differentiate between neurodegenerative diseases that might otherwise be misdiagnosed. This is particularly important for clinical trial recruitment where early symptomatic patients could potentially be recruited in error if given the wrong diagnosis, and placed in trials that they will not respond to.

The Potential of Gene Therapy to Restore Hearing Loss

Imagine that you are born deaf and live in a world of silence – what price would you pay for a new treatment that might restore your hearing?

That is the market opportunity that may be available for biotechnology and pharmaceutical companies as the basic science around congenital hearing loss starts to yield insights that could translate into new products.

Research published in the July 26, 2012 issue of the journal “Neuron” by Omar Akil from UCSF and colleagues at the University of Pittsburgh and Ohio State University, showed the ability to reverse hearing loss in mice through the use of gene therapy (viral-mediated insertion) to replace the absent vesicular glutamate transporter-3 gene (VGLUT3).

VGLUT3 is a gene involved with the transport of the neurotransmitter glutamate that is required by inner hair cells in order to generate neural responses to sound. Mice lacking VGLUT3 can’t hear.

Insertion of the VGLUT3 gene into mice cochlear cells resulted in restoration of hearing that lasted for 9 months (that’s a long time for mice). The authors noted that:

“These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness.”

Over 50% of all human hearing loss is genetically based, and as tools to understand the human genome develop, scientists have been able to identify a number of genes associated with hearing loss.

Research in animal models is ongoing, with the potential in the future that we may be able to replace, repair or correct a defect a genetic mutation.

Could this lead to the restoration of human hearing? The answer is “yes”.

An accompanying editorial in Neuron by Donna Martin and Yehoash Raphael from The University of Michigan describes the work by Akil and colleagues as a major breakthrough:

“Results presented in their paper are a true breakthrough because they show that gene therapy can lead to functional recovery from sensorineural deafness. Even more exciting is the direct relevance of this work to a large population of humans who have mutations in the VGLUT3 gene.”

There remain a number of challenges before gene therapy to correct human deafness becomes a reality, but biopharmaceutical companies such as GenVec (NASDAQ: GNVC) already see the market opportunity and potential for gene therapy to correct hearing loss. Novartis have a collaboration agreement with GenVec that is worth up to $213.6M in milestone payments.

The potential of gene therapy to restore hearing loss will offer hope to many with deafness. It is an exciting area to watch as innovative science translates into personalized medicine.

References

ResearchBlogging.orgOmar Akil, Rebecca P. Seal, Kevin Burke, Chuansong Wang, Aurash Alemi, Matthew During, Robert H. Edwards, & Lawrence R. Lustig (2012). Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy Neuron, 283-293 DOI: 10.1016/j.neuron.2012.05.019

Donna M. Martin, & Yehoash Raphael (2012). Have You Heard? Viral-Mediated Gene Therapy Restores Hearing Neuron, 75, 188-190 DOI: 10.1016/j.neuron.2012.06.008

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Repetitive brain injury from high impact sports generates similar pathophysiology to traumatic brain injury in soldiers blown up by IEDs

Several retired American Football stars have ended up with chronic traumatic encephalophy (CTE), previously known as dementia pugilistica. It’s similar to Alzheimer’s disease in that the brain ends up with neurofibrillary tangles.

Science Translational Medicine Cover May 16CTE has also been seen in soldiers who have experienced blast induced traumatic brain injury (bTBI) from improvised explosive devices (IEDs). I previously wrote on this blog about how nanotechnology may revolutionize the detection of TBI using a nanomaterial that changes color.

Research published in the May 16, 2012 issue of Science Translational Magazine by Lee Goldstein and colleagues from the Molecular Aging and Development Laboratory at Boston University & other institutions, compared CTE neuropathology in blast-exposed military veterans and athletes with repetitive concussion injury.

For the first time they have shown similarities in what happens to the brains of soldiers when they are blown up and to athletes in sports that have repeated head impacts.

The reseachers looked at 8 post-mortem brains, 4 military veterans aged 22 to 45 with a history of blast exposure were compared to 4 athletes aged 17 to 27 who were either American Football players or, in one case, a wrestler. Despite the small sample size, the results showed similar brain trauma in the two groups:

“the effects of blast exposure, concussive injury, and mixed trauma (blast exposure and concussive injury) were indistinguishable.”

It is worth noting that the brain neuropathysiology seen was different from that seen with Alzheimer’s disease (AD).

The researchers went on to develop a mouse model that could be used to investigate the link between blast exposure, brain neuropathology and behavior.  I encourage you to read the STM paper for full details on this.

Some of the key findings of their mouse experiments were:

  • Blast exposure induces traumatic head acceleration in a blast neurotrauma mouse model
  • Single-blast exposure persistently impairs axonal conduction and long-term potentiation of activity-dependent synaptic transmission in the hippocampus
  • Single-blast exposure induces long-term behavioural deficits that are prevented by head immobilization during blast exposure.

The authors conclude that their results “provide compelling evidence linking blast exposure to long-lasting brain injury.”

What this research suggests to me is:

  • An ongoing need to design safer head protection for athletes and soldiers
  • The need to monitor and detect traumatic brain injury (I wrote last year about how nanomaterials were being developed to monitor blast exposure)
  • Need to identify those genetic factors (e.g. carrying the APOE e4 allele leads to a high risk of developing Alzheimer’s disease) that may lead to a heightened risk of developing dementia or CTE.

The paper by Goldstein and colleagues in STM is well worth reading if you have an interest in this area and the debate about the safety of young people in high-contact sports.

Reference

ResearchBlogging.orgGoldstein, L., Fisher, A., Tagge, C., Zhang, X., Velisek, L., Sullivan, J., Upreti, C., Kracht, J., Ericsson, M., Wojnarowicz, M., Goletiani, C., Maglakelidze, G., Casey, N., Moncaster, J., Minaeva, O., Moir, R., Nowinski, C., Stern, R., Cantu, R., Geiling, J., Blusztajn, J., Wolozin, B., Ikezu, T., Stein, T., Budson, A., Kowall, N., Chargin, D., Sharon, A., Saman, S., Hall, G., Moss, W., Cleveland, R., Tanzi, R., Stanton, P., & McKee, A. (2012). Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model Science Translational Medicine, 4 (134), 134-134 DOI: 10.1126/scitranslmed.3003716

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TEDMED 2012: Francis Collins on how to brings drugs to market faster

If like me, you didn’t attend TEDMED in Washington DC, then you can now watch videos from the TEDMED 2012 conference.

With my interest in innovation and how to bring drugs to market faster, one video that caught my attention was by Francis Collins MD, PhD, Director of the National Institutes of Health (NIH) who talked about the challenges of going from basic science (fundamental knowledge) to its application.

In his presentation, Dr Collins talks about how it can take 14 years of research and the screening of 10,000 compounds to bring 1 new drug to market.

Drug Development Pipeline

How can we do better was the theme of his presentation, how to make drug development go faster and be more successful?

One way to go faster is to take advantage of technology such as the ability to read the human genome, the cost of which has dramatically decreased.

Cost of Sequencing Human Genome

Using progeria as an example, Dr Collins discussed how older drugs may be effective in new indications.  Drug repurposing will be a partnership between academia, government, private sector and patient organizations, he said.

NIH Drug Repurposing Table

He also discussed how human cells can be used to test whether drugs are going to be safe and effective before any animal or human experiments are done.

The opportunities for drug development are exciting if the right partnerships, talent and funding are put in place. It will be interesting to see how Dr Collins vision plays out over the next few years.

I expect that as we learn more about the human genome, and better understand molecular targets, we will see more new drugs come to market that make a difference in the lives of patients.

The video below is well worth watching:

AUA 2012 Twitter Conference Coverage #URO12

American Urological Association 2012 Annual MeetingAlthough there is a lot of buzz around ASCO 2012 in a few weeks time, this weekend sees the start of the annual meeting of the American Urological Association (AUA) in Atlanta.  AUA 2012 runs from May 19-23 at the Georgia World Congress Center.

A few of the sessions that caught my attention include:

  • Basic Science Symposium on Nanomedicine and its application to urology. Several speakers will discuss how nanoparticles can be used for drug delivery, imaging and as therapeutic tools.
  • Society for Basic Urologic Research (SBUR) and Society of Urologic Oncology (SUO) joint meeting on personalized medicine and novel targets for cancer therapy.

For those of you who missed AUA 2011, you can obtain a flavor of the meeting from Sally Church’s video that was published on Pharma Strategy Blog.

http://youtu.be/ORhfugi-pxs

If you can’t be in Atlanta, you can follow updates from the conference on Twitter (hashtag #UR012). A few people to follow at the meeting include @cooperberg_ucsf, @daviesbj, @MaverickNY, @NeuroUroGastro.

We are aggregating the #URO12 tweets so you can easily catch up on the conversation and news below:

AACR 2012: ABT-199 is a new Bcl-2 inhibitor with potential in Chronic Lymphocytic Leukemia

The New Drugs on the Horizon session at the recent annual American Association for Cancer Research (AACR) meeting in Chicago showcased several drugs that I expect we will be hearing more of in the future.  I previously wrote about AZD3514 in prostate cancer.

Another small molecule that particularly impressed me in this AACR session was ABT-199, a potent and selective inhibitor of Bcl-2. Steven Elmore from Abbott Laboratories presented impressive early data from an ongoing phase I trial in patients with chronic lymphocytic leukemia (CLL).

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Bcl-2 is a signaling pathway for the regulation of apoptosis

Bcl-2 is part of the signaling pathway for apoptosis Image Source: WikiCommons Author: Cybertory

The Bcl-2 (B-cell lymphoma 2) gene has a potential involvement in many cancers including melanoma, breast cancer, CLL and lung cancer.

As an example, Sally Church, PhD on Pharma Strategy Blog has written about how the Bcl-2 family protein Mcl-1 is involved BRAF resistance, and how RNA silencing of Mcl-1 enhances ABT-737 mediated apoptosis in melanoma.

Inhibition of Bcl-2 presents a particularly promising target in CLL

Anthony Letai (Dana-Farber Cancer Institute) wrote in “Blood” last year, “antagonizing function of Bcl-2 is an attractive goal in chronic lymphocytic leukemia (CLL) and other lymphoid malignancies.” (doi: 10.1182/blood-2011-08-370346)

The Bcl-2 family of proteins regulates the programmed cell death (apoptosis) that takes place in the mitochondrion. One way that cancer cells can survive is by disrupting the apoptosis signaling pathway, and thereby avoiding cell death.

Proteins that prevent apotosis (anti-anti-apoptotic proteins) include Bcl-2, Bcl-xl, Mcl-1.  Targeting Bcl-2 can therefore induce apoptosis or cell death, and has been shown to be a successful strategy to kill leukemia and lymphoma cells.

For those interested in more information, the 2009 article (full text free) by Josyln Brunelle and Anthony Letai published in the Journal of Cell Science offers considerable insight into the Control of mitochondrial apopotosis by the Bcl-2 family” (doi 10.1242/ jcs.031682).

ABT-199 is a potent & selective Bcl-2 inhibitor

Abbott & Genetech have previously targeted Bcl-2 and Bcl-xl with navitoclax (ABT-263), currently in clinical trials for CLL & NHL.

As Steven Elmore of Abbott mentioned in his AACR presentation, the problem with navitoclax is that circulating platelet survival is dependent on Bcl-xl.  When you inhibit Bcl-xl you end up with dose-dependent thrombocytopenia in patients.  This has been a dose-limiting side effect with navitoclax.

So the goal in the development of ABT-199 was to inhibit Bcl-2, which is critical for the survival of cancer cells & avoidance of apoptosis, while at the same time not inhibiting Bcl-xl which is critical for the survival of circulating platelets.

ABT-199 is a reverse engineered version of ABT-263, that has a high affinity for Bcl-2 and lower affinity for Bcl-xl.

I captured some of the AACR live-tweets about ABT-199 in the Storify below (if you can’t see the embedded information, click here to read this on Storify).

http://storify.com/3nt/aacr-2012-abt-199-bcl-2-inhibitor

ABT-199 is an exciting new Bcl-2 inhibitor with a solid scientific rationale for success in CLL and promising initial data.  From what I saw at AACR, it is definitely a compound to watch.

According to Steven Elmore, full results from the Phase 1 CLL trial with ABT-199 will be presented at the 2012 European Hematology Association (EHA) Congress held in Amsterdam from June 14 -17.

AACR 2012: the automation of preclinical drug discovery will be a driver of innovation

There was so much good science on display at the recent 2012 annual meeting of the American Association for Cancer Research (AACR) in Chicago that any blog posts are but a personal snapshot or postcard.

Bill Sellers VP Global Head Oncology Novartis Institutes for BioMedical ResearchOne enduring image I have from the plenary presentation on “The Genetic Basis for Cancer Therapy” by Bill Sellers, VP/Global Head Oncology at Novartis Institutes for BioMedical Research was the video he showed of the robots that are used for automated cell profiling.

Imagine the advertisements that show robots being used to build cars, but now the robots are undertaking automated laboratory work in pursuit of new cancer compounds. Wow!

During his presentation, Sellers described how Novartis have built a robust preclinical translational infrastructure.

He went on to say that, “many experiments we have done in the past, and even many molecules that were put in the human, really were only profiled against a limited number of preclinical models such as one cell line.”

In order to make preclinical data more reproducible, Novartis had the goal to move from testing against one cell line to testing against an encyclopedia of cell lines.

This has now become a reality with the launch of the Cancer Cell Line Encyclopedia (CCLE) in collaboration with the Broad Institute. The CCLE was recently announced by Novartis in a media release, and details were published online on March 28, 2012 in a letter to “Nature” (doi:10.1038/nature11003).

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

As described in “Nature”:The Cancer Cell Line Encyclopedia (CCLE) is a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines.

When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity.”

Sellers noted in his AACR plenary presentation that the key to using the CCLE is for profiling and to:

“identify subsets of cancer cell lines that are sensitive to a given therapeutic versus those that are not. And then better yet to identify the markers of sensitivity that are differentially expressed or present in the sensitive versus insensitive cell lines.”

Novartis Institute for Biomedical Research Automated Robotic Drug DiscoveryTo do this, Sellers described how Novartis have built a robotic system that e.g. automates cell profiling.  In approx 3 months with this system we can profile 600 cell lines for about 1500 compounds, he said.

This type of preclinical automation is speeding up cancer drug discovery through the ability to more rapidly identify those compounds that are associated with and have activity against different mutations.

In my view, this will drive innovation through the effective and efficient screening of potential new cancer compounds, with the result that only those compounds with demonstrable promise progress.

AACR have made Bill Sellers plenary presentation available as a free webcast from the 2012 annual meeting (along with several others).  I encourage anyone interested in how cancer biology is driving cancer drug development to watch this.

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