Apr 26 / DNA Dude

Two Lauras and the future of breast cancer clinical trials

Last week at the annual AACR meeting in Washington DC, I had the pleasure of listening to the inspiring talks of “The Two Lauras.” While certainly not getting as much attention as the volcano, the vision and efforts of these two women are quietly catalyzing what might be THE most important revolution to occur in clinical trials of breast cancer therapeutics. This program has the potential to improve and expedite the approval process for promising, life saving cancer drugs.  In an overburdened healthcare system desperate for breakthroughs, economically improving healthcare for thousands of breast care patients would be a nice start.

I am referring, of course,  Laura Esserman, Ph.D. MBA and Laura van ‘t Veer, Ph.D. These women are pushing the envelope to transform clinical research breakthroughs into clinically relevant programs. Their relentless conviction and persuasive attitudes of “Just say YES” is both refreshing and effective in terms of the results which have been accomplished to facilitate the launch of  I-SPY2.

Laura Esserman is Professor of Surgery and Radiology at UCSF and director, Carol Franc Buck Breast Care Center. As documented by her numerous publications and awards, Dr. Esserman’s years of experience in research, surgery and radiology have given here a unique perspective on both the opportunities and struggles ahead to change current standards of care for breast cancer patients.

Laura van ‘t Veer recently joined UCSF as Director of Applied Genomics  from the NKI in The Netherlands where she was the head of diagnostic oncology. At the NKI, along with Rene Bernards, their pioneering work resulted in the landmark NEJM paper describing a 70 gene signature as a predictor of survival in breast cancer. This signature went on to become MammaPrint, the world’s first FDA cleared IVDMIA as an early test to assist physicians and patients in chemotherapy decisions.

Together, these women, along with a dedicated team, initiated the I-SPY 1 trial. Following its success, phase II, the novel, I-SPY 2 multi-therapeutic breast cancer trial is already under way and just may change cancer therpeutic clinical trials forever.

The I-SPY 2 trial

I-SPY 2 is the first adaptive design clinical trial program of its kind which incorporates multiple therapeutic agents, biomarkers and technology platforms for analysis among the working teams. The trial has been collaboratively designed to function within the FDA’s critical path initiative guidelines with the shared vision of accelerating approval of new therapies.. The Research process is highly collaborativenacross all sectors and an ideal model for the Biomarker Consortium.

I-SPY 2 has the potential to:

  • Reduce time of conclusive results
  • Accelerate learning
  • Reduce patients/volunteers required
  • Reduce cost of conducting trials
  • Increase collaboration & data sharing among researchers, technology and pharmaceutical companies

I-SPY 2 is revolutionary not evolutionary. For the first time, big pharma, technology platform companies, a diagnostic company and major research institutions have come together under a collaborative umbrella with the FDA for a novel, multi-therapeutic clinical trial. This ongoing trial, which can adapt and even simultaneously evaluate up to five therapeutics, could give hope to thousands of women around the world who are at high risk of metastatic breast cancer.

A great thing about this trial from the start is the pervasive passion to the program. All participants have displayed commitment through compromise, transparency and ownership of risk. Stakeholders in both commercial and research institutions have created and agreed to research, intellectual property and publication processes with the fNIH , “the “honest broker” as David Wholley likes to say. These mutually agreed upon rules have been developed in careful collaboration to ensure everyone’s best interests are maintained. This alone is an amazing feat considering the number of commercial, research and governmental institutions involved.

The commitment of the participating drug companies is clear. This open transparency and cooperation would simply not have happened a decade ago. Kudos to “The Two Lauras” for patiently (and impatiently when roadblocks occurred) motivating, educating, clarifying and moving everyone towards the common goals of I-SPY 2.

The FDA has also embraced this new approach in anticipation of success both in speed and reduced cost to get much needed, more efficacious therapeutics to the market faster. At fNIH, David Whooley tirelessly battled and negotiated to meet the needs of all stakeholders involved. Kudos to David as well for the thankless job of playing both good-cop/bad-cop and bad-cop/bad-cop in multiple agreement negotiations necessary to make this happen.

For now, we will all watch. But to be sure, there will be more I-SPY-like trials to come.

Apr 8 / DNA Dude

Cancer tumor profiling. So many questions…. so little sample….

During my first week as an “-ostics guy” at Agendia, I met Rene Bernards. Wow… what a rush. In the next hour, Rene proceeded to elaborate on many topics which yet again, changed my thinking around “applied -omics” as it relates to molecular diagnostic (MDx) patients tests with validated, clinical utility. In particular that day, I was intrigued by Rene’s comment, “In cancer, no matter how many tests and technologies emerge, there will only be one precious tumor sample.” Rene then went on to talk about the NKI’s decision, (very visionary by the way), to save fresh tissue tumor samples as apposed to the more convenient formalin fixed (FFPE) route.  His view is that technology advancements will bring new answers to questions buried in those samples, but the answers will only be as good as the quality of undamaged information buried within the sample. (Kind of a “duhhh” thing for me now, but this was the first of many important points which confirmed see just how much Rene, Laura and Bernhard “got it”, why they were going to do great things, and how they were able to form Agendia.)

But back to the tumor sample….

Sample Storage Analogy - Tumors vs Meats
Whether acquired through a biopsy or surgery, this small, piece of “renegade human tissue gone wild” can be the ultimate gating factor in tumor profiling. The tumor sample’s journey begins with the patient through either surgery or biopsy, completely reliant on the “buy-in” of its value from the person involved in its removal. While surgeons typically provide samples from tumor removals, Biopsies can be performed manually, semi-manually and even fully automated. Either way, after removal the clock begins ticking as information begins degrading immediately. The first to go are certain chemicals and enzymes which simply do not like so the air. Shortly following are less stable proteins and RNA transcripts. The DNA is pretty stable for now.  However, handling, time and sample fixation in a stablizer such as RNALater or formalin is critical. Combined with the need for proper sample preparation for further testing, margins of error can be slim.  As compared to blood tests, in tumor profiling, there may be no sample for a second re-test. The attention to detail and even regulation of process is a key criteria for success in breast cancer evaluation. Why is this important? Well….. the questions and quality of those questions asked of a patient tumor sample may determine the length and quality of life of a patient by determining the need for chemotherapy or the  likelihood of responding to a particular therapy.

It is astounding how recent advancements in low cost, high throughput genomics have driven down costs, increased sample profiling speed and capacity. Molecular diagnostics companies are routinely running tens of thousands of MDx tests which would have been considered unscaleable in the past. Service companies like, Complete Genomics claim they can even sequence 1000’s of human genomes at several orders of magnitude below costs a genome sequence as compared to my Celera days just over a decade ago. Resequencing of genomic DNA matched normals, DNA somatic mutations cancer genomes, of course free-floating, protein factory instruction sets (mRNAs) and even emerging “pathway machinery switches” (siRNAs) which we are just beginning to understand. Not to mention exciting emerging protein marker technologies such as Lee Hood’s MS-protein approaches which are being incorporated into (Integrated Diagnostics). BTW congrats to their new CEO Al Luderer.

The point is, all of these technologies will emerge, and biology will make sure no one technology will dominate. So, how are we going to ask all these questions, and which combination of technologies will produce clinically relevant answers which will lead to next generation of IN-VITRO DIAGNOSTIC MULTI-VARIATE INDEX ASSAYs, (IVDMIA’s)? These tests are happening and more will follow. All good stuff. However, a bottleneck to these emerging tests lies in the tumor sample. Quantity, quality, storage and preparation. Period. And to make it even more interesting, early detection technologies are decreasing the size of the tumors we are able to acquire.

Tumor Sample & Patient Treatment

So where will all this lead? Dunno. But some good people out there are on the case. More later about them and the efforts under way which are bring the change.

On a final note…. TumorTissue Banking. I have become a big fan of tumor tissue banking. From my prior days and Gene Logic and watching early efforts of companies like Ardais, who simply may have been ahead of their time, I have come around to a new appreciation of its potential. And why not? We save umbilical chords for kids and now, even baby teeth. In hopes of future stem cell advancements. Why wouldn’t I want to save my own cancer cells or those of someone I love the way I see things going. Just something to think about.

The notion of banking tumor sample for research and retrospective studies is not a new concept. Many successful research programs and clinical trials have and will be enabled through well-established accrual programs linked to valuable patient follow-up and survival data. However, if we wish to accelerate advancements of patient healthcare management solutions, a fundamental shift must occur our thinking around tumor profiling. Among other things, this will require new partnerships as no one company or research institute is likely to solve this emerging challenge. Partnerships which drive co-development of these solutions will dominate and accelerate the impact and adoption of emerging, life saving tests. More on this later.

Jan 15 / DNA Dude

DNA. The Ultimate Business Experience.

First off….don’t worry if you don’t understand any of this stuff yet… I will fill in gaps in the education section of DNADude.com later.

PCR, sequencing, the human genome as a business model, gene expression databases as a business model, nanofluidics & high throughput everything, synthetic biology and now, molecular diagnostics in cancer prediction.  As exciting as this history has been, it is dwarfed by the excitement of what is to come.

The ride started in the late 80’s as the Irvine strawberry fields were paved for business growth. My roomate and I were the  Irvine Xerox rep duo. I saw an ad for lab equipment sales, inteviewed well thanks to Xerox, and started selling for Perkin Elmer. Then one day, they said I was selling a new product, sent me to Emeryville for a day training at Cetus, and… POOF, I was the 1st PCR rep in SoCal selling this new thing called PCR. Hell, it was easy. A DNA XEROX Machine….PCR made copies of short pieces of DNA, lots of them, right? Needle copies in the haystack, easy to find, value prop simple. In the day, a copier was to a secretary and carbon paper, what a Perkin-Elmer/Cetus Thermal Cycler was to a grad student with a stop watch and water bath …. and….BOOM…genetics….off to the races…even though the “-omics” era was still over a decade away.

From PCR, the ride continued with ABI, automated sequencing and genome centers….

Then off to the human genome with Craig and company. It was quite the time to be a “business roadie” for a “genomics rock star”…… (plenty blogs to share from that ride…)

Now… MDx and oncology, Ph.D.’s & M.D.’s trying to bridge it together. A fascinating ride, still early days, and promises of personalized medicine which will happen, have to happen. The whole field of cancer, is undergoing fundamental paradigm changes and  is as fascinating as anything I have done.

Be warned… I use off-the-wall analogies and concepts to get my point across. A friend once told me its a “southern thing” as my roots are in North Carolina. My commitment is to enlightening the masses, and in the spirit or Richard Feynman, have explained more than one DNA concept on a bar napkin to those who glaze over if I really explain the details of the science.

OK, that’s a start and the “maiden blog.” Stay tuned….