Education and Training:
B.S., Biology, Wright State University, Dayton, OH (1982)
M.D., The Ohio State University, Columbus, OH (1986)
Internship, Department of Medicine, Duke University (1986-87)
Residency, Department of Medicine, Duke University (1987-89)
Fellowship, Division of Oncology, University of Washington, Seattle, (1989-94)
|C. Anthony Blau, M.D.
Professor of Medicine
Division of Hematology
University of Washington School of Medicine
Co-Director, University of Washington Institute for Stem Cell and Regenerative Medicine
Co-Director, Stem and Progenitor Cell Biology Program, Fred Hutchinson/University of Washington Cancer Consortium
Institute for Stem Cell and Regenerative Medicine
University of Washington Campus Box 358056
815 Mercer Street, Rm N535
Seattle, WA 98109
Phone: (206) 685-6873
Fax: (206) 221-0531
Institute for Stem Cell and Regenerative Medicine: https://depts.washington.edu/iscrm
Blau lab website: http://depts.washington.edu/blaulab
CURRENT CLINICAL INTERESTS
General hematology, hemoglobinopathies, hematological malignancies
Hemopoietic stem cell biology, gene therapy, globin gene regulation,
personalized approaches to cancer treatment
and the Pluripotent
Mouse embryonic stem cells (ESC) are derived from the pre-implantation
embryo. In 2007, two groups described a new type of mouse stem cell
derived from the post-implantation embryo, called the epiblast stem
cell (EpiSC) (Tesar
et al., Nature 2007). Although EpiSC can form most tissues,
they differ from ESC in their morphological appearance, culture
requirements, and gene expression profile. Interestingly, human ESC
are similar in their appearance and culture requirements to EpiSC.
Our collaborator, Carol Ware, discovered that a low, narrow
concentration of the histone deacetylase Inhibitor, sodium butyrate,
can support the self renewal of ESC from humans, mice, and non-human
et al., Cell Stem Cell 2009). Butyrate appears to induce a
change in stem cell state. Gene expression profiling suggests that
human ESC pulled backward to an earlier developmental stage, whereas
mouse ESC are pushed forward.
CB, Chien S, and Blau CA. Slow,
Controlled-Rate Freezing Improves Human Embryonic Stem Cell Survival.
Biotechniques 38:879-883, 2005.
CB, Nelson, AM, and Blau CA. A
Comparison of NIH-Approved Human Embryonic Stem Cell Lines. Stem
Cells 24:2677-84, 2006.
L, Schulz TC, Sherrer ES, Dauphin DS, Shin S, Nelson AM, Ware CB, Zhan
M, Song C-Z, Chen X, Brimble SN, Amanda M, Galeano MJ, Uhl EW, Damour
KA, Chesnut J, Rao MS, Blau CA and Robins AJ. Self-renewal
of human embryonic stem cells requires insulin-like growth factor-1
receptor and ERBB2 receptor signaling. Blood 110:4111-9,
CB, Wang L, Mecham BH, Nelson AM, Dauphin DS, Buckingham B, Bar M, Lim
R, Askari B, Gartler SM, Shen L, Issa J-P, Tewari M, Lamba DA,
Pavlidis P, Duan Z, and Blau CA. Histone
Deacetylase Inhibition Elicits an Evolutionarily Conserved
Self-Renewal Program in Embryonic Stem Cells. Cell Stem Cell
to 40% of patients with cancer are anemic at the time of diagnosis, and a
large body of evidence indicates that anemia is a key predictor of survival,
independent of disease severity. The mechanism whereby anemia impairs outcome
in patients with cancer is not well understood, but has been attributed in
part to tumor hypoxia, which can select for tumor cells resistant to
chemotherapy and radiation therapy. This rationale helped to lay the
groundwork for using Epo for the treatment of anemia in patients with cancer.
Recombinant Epo first received FDA approval for the treatment of
cancer-related anemia in 1993, and subsequently grew to become the most
commercially successful drug in all of oncology. However, the results of Phase
III clinical trials now indicate that Epo can reduce survival rates and
promote tumor progression in cancers of the head and neck, breast and in most
common forms of lung cancer. Although some of these trials are not yet
published, and several of the published trials have been criticized for design
limitations, the FDA issued a "black box" warning for Epo in March
2007. How Epo stimulates tumor progression is uncertain, but may reflect
off-target effects (figure, below). EpoR transcripts have been detected in
multiple primary cancers including tumors of the breast, head and neck, and
non-small cell lung. Some reports have documented Epo-induced proliferation,
invasion, migration, and protection from chemo- and radio-therapy in various
cancer cell lines. Moreover, blocking endogenous Epo can inhibit breast cancer
growth and tumor vascularization in a rat model, and ovarian and uterine
cancers in mice. Finally, EpoR expression and function in endothelial cells is
well-documented, and Epo might stimulate tumor progression by promoting tumor
Erythropoietin Induced Tumor Progression An Off-Target Effect?
From Nature Medicine,
of the phase III trials suggesting that Epo might promote cancer progression,
was ENHANCE, a trial of 351 patients with head and neck cancer (Henke
et al., Lancet 2003). ENHANCE demonstrated a shorter locoregional
progression free survival (LPFS) in head and neck cancer patients randomized
to Epo rather than placebo during radiotherapy. ENHANCE incorporated patients
who underwent complete, partial or no resection of tumor prior to
radiotherapy. Adverse effects of Epo were confined to patients with residual
tumor at the time of radiotherapy. We developed an assay to measure mRNA
levels of genes implicated (EpoR, Jak2, Csf2rb, Hsp70) or not implicated
(Krt5, Cd44) in Epo signaling in formalin-fixed paraffin-embedded (FFPE)
tumors, and tested 136 tumors from ENHANCE. We compared LPFS between patients
with tumors expressing above- versus below-median levels of the aforementioned
mRNAs using the log rank statistic. Sufficient RNA for EpoR measurements was
available in 101 tumors and EpoR varied over a 30-fold range. There was no
association between tumor EpoR level and LPFS across all 101 patients. However
in patients with unresected tumors (n=28), above-median EpoR mRNA levels were
associated with significantly poorer LPFS if randomized to Epo rather than
placebo (p=0.02, n=14). A similar association was observed in patients with
above-median levels of Jak2 mRNA (p=0.02, n=18) or below-median levels of
Hsp70 (p=0.01, n=20). LPFS was not significantly different when comparing Epo-treated
patients with above-median mRNA levels to Epo-treated patients with
below-median levels. EpoR mRNA levels can be reliably measured in FFPE tumors.
These associations merit evaluation in larger numbers of tumors from other
Phase III trials.
CA. Erythropoietin in
Cancer: Presumption of Innocence? Stem
Cells 2007; 25:2094-7.
CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE,
Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold
PR, Dorr DA, Kunzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M. Venous
Thromboembolism and Mortality Associated with Recombinant Erythropoietin and
Darbepoietin Administration for the Treatment of Cancer-Associated Anemia.
CP, Lowe KA, Valliant-Saunders K, Kaiser JF, Mattern D, Urban N, Henke M, Blau
Erythropoietin-Associated Tumor Progression Using Archival Tissues from a
Phase III Clinical Trial. Stem
Cells 27:2353-61, 2009.
CP, Valliant-Saunders K, Blau CA. Limitations
of a murine transgenic breast cancer model for studies of
erythropoietin-induced tumor progression. Translational
Oncology 2010 Jun 1;3(3):176-80.
Regulated Cell Therapy
are developing a new generation of cell therapies that involves placing cells
under the "remote control" of small molecule drugs. Over the past
decade we have completed much of the ground-work establishing the feasibility
of this approach. We believe that the approaches we are developing today will
be commonplace 100 years from now (see the last chapter of "Thomas'
Hematopoietic Cell Transplantation," written by Ernie Beutler), but we
are most interested in pursuing approaches with (hopefully) nearer-term
target effects constrain the clinical applicability of growth factors.
The safety and efficacy of a drug are determined by two forms of specificity:
specificity of the drug for its target (usually a protein), and specificity of
the drug target in the pathogenesis of the disease being treated. Side effects
arise when either type of specificity falls short of physiologically dictated
thresholds, phenomena collectively referred to as "off-target"
effects. Although off-target effects plague all drug development, their impact
on the clinical use of hematopoietic growth factors provide a case-in-point,
and a little explored rationale for genetic manipulation.
major hematopoietic growth factors in clinical use today, erythropoietin (Epo),
granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage
colony stimulating factor (GM-CSF) were all approved by the US Food and Drug
Administration (FDA) more than 15 years ago. Since then no growth factors with
novel biological activity have gained widespread use, a situation almost
entirely attributable to off-target effects. For example, none of the many
potential clinical uses for recombinant stem cell factor (SCF) were realized
because its receptor (c-kit) is expressed not only in primitive hematopoietic
progenitors, but also in mast cells, causing significant allergic reactions in
10 - 20% of patients. Fibroblast growth factors (FGFs) further illustrate the
problem. 23 different FGFs bind 7 different receptor isoforms that are
variably expressed in all tissues. Most FGFs activate more than one type of
FGF receptor, leading to one type of off target effect. Furthermore, even when
an FGF specific for a given receptor is used, the receptor is invariably
expressed in multiple cell types, producing a second type of off target
effect. Thus clinical trials of FGFs have yielded disappointing results. Over
the past decade we have been developing a system that has the potential to
circumvent off-target effects.
An important obstacle to cell therapy is the loss of control over cells that
have been transplanted. We used previously described technology to develop a
way to regulate the proliferation of engineered cells using a growth factor
receptor modified to substitute its normal ligand-binding site with the
binding site for a drug called a chemical inducer of dimerization (CID). The
CID brings together two copies of the artificial receptor, triggering its
activation and leading to cell proliferation, thereby mimicking the effect of
a growth factor.
1. Left panel A proliferation switch consisting of a receptor and a
dimerization domain is activated upon addition of a CID, thereby mimicking the
effect of growth factors. Right panel: In vivo selection of genetically
modified cells using CIDs. The vector may encode a therapeutic gene in
addition to the CID selectable gene. Following infusion of transduced cells,
the CID specifically induces genetically modified cells to proliferate.
First generation CIDs capitalized on the interaction between a drug, FK506,
and its naturally occurring intracellular target, FKBP12, and dimerization was
induced by covalently linking two copies of FK506 to generate a new ligand
called FK1012. To dramatically reduce undesired interactions between FK1012
and endogenous FKBP12, second generation CIDs were developed using a
"bump and hole" approach. These new CIDs (such as AP1903 and
AP20187) contain chemical modifications ("bumps") that preclude
binding to endogenous FKBP12, but which can be accommodated by a modification
of FKBP12 to introduce a pocket ("hole") via a single amino acid
substitution (F36V). AP1903 was well tolerated in a Phase I study in normal
human volunteers. This approach has a number of advantages, many of which are
described in greater detail below. One advantage is its generalizability. A
single drug can be used to regulate hundreds of different signaling molecules,
to elicit a variety of cellular responses. In previous studies we have used
signaling domains taken from the erythropoietin receptor, GCSF receptor,
gp130, flt-3, c-kit, Mpl, fibroblast growth factor receptor-1 (FGFR-1), and
the 4 Janus kinase family members to induce CID-dependent proliferation. A
second advantage is its versatility, allowing for regulated proliferation both
in vitro and in vivo. A third advantage is its anticipated lack of
immunogenicity, because CID responsive proteins can be entirely human in
origin, in contrast to virtually all other regulated systems that rely on the
expression of foreign proteins, and are therefore susceptible to immune
responses. A fourth advantage is its wide applicability, with examples of
CID-regulated proliferation ranging from myoblasts, hepatocytes and pancreatic
islet cells, to primary hematopoietic cells, suggesting that CID-regulated
approaches might provide an operating system for cell therapy. Hematopoietic
applications enjoy a fifth advantage, pleiotropy, because different growth
factor signaling domains can elicit different hematopoietic responses,
allowing CIDs to regulate hematopoiesis in ways unachievable with conventional
growth factors. A sixth advantage of this approach is its specificity. In
contrast to conventional growth factors which can bind off-target receptors,
or receptors expressed by off-target cell types, CIDs can deliver specific
signals to specific cell types. It is this feature that is most relevant for
the work described below. We are applying CID regulation to a recently
recognized problem related to off-target effects of Epo in patients with
cancer related anemia (LINK).
platform for cell therapy.
Preclinical studies have shown that CIDs can be used to regulate the
proliferation of pancreatic islet cells for the treatment of diabetes, muscle
cells for the treatment of heart failure, and hepatocytes for the treatment of
liver disease. A derivative of this approach can be used to bring apoptotic
proteins under pharmacological control, allowing for the CID induced killing
of genetically modified cells. Thus CID regulation of various signaling
molecules can provide a general operating system for cell therapy (Miller
& Blau, Gene Therapy 2008).
for the Treatment
Red Cell Production.
We have used CIDs, in combination with a derivative of the thrombopoietin
receptor (F36VMpl), to direct the Epo-independent production of red blood
cells in mice in dogs followed for longer than six years (reference 16 and
data not shown) and in human CD34+ cells ex vivo and following transplantation
into immune deficient mice. Representative results from one of our mouse
studies are shown in Figure 2 (below). While our vector expresses F36VMpl in
all hematopoietic lineages, the predominant effect of CID administration is to
enhance red blood cell production.
Figure 2: CID regulated erythropoiesis. Left panel: Effect of AP20187
administration on mean percentages of GFP+ red cells (RBCs), in 5 mice
transplanted with congenic marrow cells transduced with an MSCV-based vector
encoding both F36VMpl and a GFP marker and treated with 4 separate courses of
AP20187 beginning 4 months post transplant (left) or monitored for 8 months,
then treated with AP20187 (right). Arrows indicate 3 day courses of AP20187
(10 mg/kg/day). Error bars denote standard deviations. Right panel: Spun
hematocrits from 8 mice one week following a 7 day course of AP20187. GFP:
Mice transplanted with marrow cells transduced with a control vector, with
hematocrits ranging from 40-46%; F36VMpl: Mice transplanted with the F36VMpl
vector had hematocrits ranging from 56-62% (p=0.003).
erythrocytosis can down-regulate endogenous Epo.
One of the theoretical benefits of using CIDs in patients with cancer is the
decline in endogenous Epo that is expected to accompany a CID-triggered
increase in red cells. We have demonstrated that this prediction holds true in
an anemic mouse model. Pyruvate kinase (pk)-deficient mice have a marked
hemolytic anemia and dramatically reduced red cell survival. We established a
chimeric mouse model in which 90% of marrow cells were of pk-deficient host
origin, whereas the remaining 10% of cells originated from normal donor marrow
cells that had been transduced with a vector encoding F36VMpl immediately
prior to transplantation. CID administration specifically directed the
expansion of the normal donor erythrocytes, promoting an increase in
circulating red cells, (Figure 3A, below), and a decline in circulating Epo
levels (Figure 3B, below).
Figure 3. Epo levels decline following CID administration. Three of six pk
deficient mice containing ~10% MSCVGFPiresF36VMpl
transduced normal donor marrow cells were assigned to treatment with AP20187
10 ยตg/kg, 3 days a week for 2 weeks, then every day for 2 weeks, while the
remaining 3 mice provided non-CID treated controls. (A) Erythrocyte numbers
and the percentage of GFP-positive erythrocytes increased in CID treated mice
(+) relative to untreated mice (-). (B) Epo levels were measured in the 6
mice, 3 CBA/N mice, and 3 CBA-Pk-1slc/Pk-1slc mice (PK-/PK-).
Treated mice had Epo levels between those of CBA/N mice and those of CBA-Pk-1slc/Pk-1slc
mice. *Data from 1 of the untreated mice with an Epo level of 570 mU/mL was
not included in the bar chart.
CID-dependent red cell production is Epo-independent.
To test the premise that CID- stimulated erythropoiesis is not dependent on
the presence of Epo, F36VMpl-transduced human CD34+ cord blood (CB) cells were
evaluateded for their ability to generate red cells in response to CID
treatment, in the presence or absence of the Epo antagonist, soluble
recombinant human EpoR (srhEpoR). Results are shown in Figure 4 (below)..
4: CID-dependent red cell production is not affected by Epo blockade. Cord
blood CD34+ cells were transduced with a lentivirus vector encoding F36VMpl,
then cultured in the presence (+) or absence (-) of Epo (5 U/ml), AP20187 (100
nM), and the competitive Epo antagonist, soluble recombinant human EpoR (at
the concentration indicated). Cells counts (left panel) and flow cytometry
(right panel were performed on day 12. Results show that AP20187 dependent red
cell production is not impaired by Epo ablation.
cultured in the absence of Epo did not proliferate (Figure 4, above) and
retained expression of the myeloid marker CD33 (Right Panel, above). Epo (5 U/mL)
induced proliferation (66.2-fold in 12 days) and CD33 expression was lost as
the cells differentiated into glycophorin A+ erythroid cells. Addition of a
competitive inhibitor of Epo binding (soluble human EpoR extracellular domain
[shEpoR]) at a concentration of 2.7 μ/mL completely blocked Epo-dependent
proliferation and, similar to cells cultured without Epo, CD33 expression
persisted. Addition of CID (100nM AP20187) (without Epo) promoted cell
expansion (89.8-fold in 12 days) and differentiation as glycophorin A+
erythroid cells, findings that were unchanged in the presence of shEpoR. These
data suggest that F36VMpl does not require Epo signaling to support the
proliferation and differentiation of human erythroid progenitor cells.
of CID regulated red cell production in patients with cancer.
Developing methods for converting red cell production from dependency on Epo
to dependency on CIDs would provide at least 3 advantages in patients with
cancer by i) circumventing the need for exogenous Epo; ii) reducing endogenous
levels of Epo via feedback inhibition of renal Epo secretion (Figure 5,
below); and iii) opening the potential for combining with Epo antagonists to
achieve total ablation of Epo signaling, analogous to androgen blockade for
prostate cancer or estrogen blockade for breast cancer, possibly providing a
new way to treat a wide range of malignancies. Consistent with the strategy,
studies in mice indicate that Epo blockade may provide a new way of treating
cancer. A schematic depiction of the goal for our proposed approach is shown
in Figure 5, below.
Blockade for the Treatment of Cancer
Figure 5. Epo blockade for the treatment of cancer. Cancer may be sustained
not only by exogenous Epo, but also by endogenous levels of Epo that accompany
anemia. F36VMpl gene transfer followed by AP1903 administration provides a
mechanism for the Epo independent regulation of red cell production, avoiding
exogenous Epo administration, and reducing endogensous Epo levels. This
approach can also be combined with Epo/EpoR antagonists, allowing for the
complete ablation of Epo signaling (not shown).
Figure 6. Potential applications of
pharmacologically regulated cell therapy.
CA, Peterson KR, Drachman JG and Spencer DM. A
proliferation switch for genetically modified cells. PNAS USA
L, Asano H and Blau CA. Stimulating
cell proliferation through the pharmacologic activation of c-kit. Blood
L, Siritanaraktul N, Emery DW, Richard RE, Kaushansky K, Papayannopoulou Th
and Blau CA. Targeted
expansion of genetically modified bone marrow cells. PNAS USA
L, Neff T and Blau CA. Marrow
sensitization to 5 fluorouracil using the ligands for flt-3 and c-kit.
Exp Hematol. 27:520-525, 1999.
RE, Wood B, Zeng H, Papayannopoulou Th and Blau CA. Expansion
of genetically modified primary human hemopoietic cells using chemical
inducers of dimerization. Blood 95:430-6, 2000.
L, Zeng H, Otto KG, Richard RE, Emery DW and Blau CA. In
vivo selection using a cell growth switch. Nature Genet
KG, Jin L, Spencer DM and Blau CA. Cell
Proliferation Induced by Forced Engagement of c-Kit and Flt-3. Blood
H, Masuko M, Jin L, Neff T, Otto KG and Blau CA. Receptor
specificity in the self-renewal and differentiation of primary multipotential
hemopoietic cells. Blood 98:328-334, 2001.
KG, Broudy VC, Lin N, Parganas E, Drachman JG, Luthi JN, Ihle JN and Blau
localization is not required for mpl function in normal hematopoietic cells.
Blood 98:2077-2083, 2001.
ML, Otto K, Blau CA, Reinecke H and Murry CE. Control
of myoblast proliferation with a synthetic ligand. J Biol Chem
J and Blau CA. Limitations
of a mouse model of sickle cell anemia. Blood Cells Molec Dis
Z-Y, Otto KG, Richard RE, Ni S, Kirillova, I, Fausto, N, Blau CA and
Lieber, A. Dimerizer-induced
proliferation of genetically modified hepatocytes. Molecular
Therapy 5:420-6, 2002.
S, Zoller K, Masuko M, Rojnuckarin P, Yang X, Parganas E, Kaushansky K, Ihle
JN, Papayannopoulou Th, Willerford DM, Clackson T and Blau CA. JAK2,
complemented by a second signal from c-kit or flt-3, triggers extensive
self-renewal of primary multipotential hemopoietic cells. EMBO
J 21:2159-2167, 2002.
T, Horn PA, Valli VE, Gown AM, Wardwell S, Wood BL, von Kalle C, Schmidt M,
Peterson LJ, Morris JC, Richard RE, Clackson T, Kiem HP, Blau CA. Pharmacologically
regulated in vivo selection in a large animal. Blood 100:
RE and Blau CA. Selective
expansion of genetically modified cord blood cells. Stem Cells
21: 71-78, 2003.
C, Blau CA, Huang M-L, Iuliucci JD, Dalgarno DC, Gaschet J, Heimfeld S,
Clackson T, Riddell SR. Pharmacologically
regulated Fas-mediated death of adoptively transferred T cells in a nonhuman
primate model. Blood 103:1261-9, 2004.
RE, Weinreich M, Chang K-H, Ieremia J, Stevenson MM, Blau CA. Modulating
erythrocyte mixed chimerism in a mouse model of pyruvate kinase deficiency.
Blood 103:4432-4439, 2004.
S, Weinreich M, Blau CA. In
vivo selection using a JAK2-based cell growth switch. Molecular
Therapy 10:456-458, 2004.
RE, DeClaro A, Yan J, Chien S, Kiem HP, Clackson T, Andrews R, and Blau CA.
among large animal models of in vivo selection. Molecular
Therapy 10:730-740, 2004.
DW, Tubb J, Nishino Y, Nishino T, Otto KG, Stamatoyannopoulos G, and Blau
with a regulated cell growth switch increases the likelihood of expression for
a linked γ-globin gene in vitro and in vivo. Blood Cells
Mol & Dis 34:235-47. 2005.
M, Ihara K, Cummings C, Pendergrass T, Blau CA and Drachman JD. Congenital
Megakaryocytic Thrombocytopenia in Three Siblings: Molecular Analysis of
Atypical Clinical Presentation. Exp Hematol 33:1215-21,
CA, Yan J, Neades R, Navas PA, Peterson KR. g-globin
gene expression in CID-dependent multi-potential cells established from b-YAC
transgenic mice. J Biol Chem 280:36642-7, 2005.
RE, Siritanaratkul N, Jonlin E, Skarpidi E, Heimfeld S, Blau CA. Collection
of blood stem cells from patients with sickle cell anemia. Blood
Cells Mol Dis 35:384-8, 2005.
Y, Wood B, Wang L, Lintmaer I, Guo W, Papayannopoulou Th, Harkey M, Nourigat
C, Blau CA. Anatomical
Compartments Modulate the Response of Human Hematopoietic Cells to a Mitogenic
Signal In Vitro and In Vivo. Stem Cells 24:908-17, 2006.
MA, Lintmaer I, Wang L, Liggitt D, Harkey M, Blau CA. Growth
Factor Receptors as Regulators of Hematopoiesis. Blood
CA, Blau CA. Using
Gene Transfer to Circumvent Off-Target Effects. (2008) Gene
Therapy 15:759-64, 2008
of the fundamental questions of the post-genome era is: How does genotype (an
organism's genetic structure) translate into phenotype (an observable
characteristic)? Our genetic information is contained in 23 pairs of
chromosomes. The 46 chromosomes are arranged not in straight lines, but in a
tangle, like a plate of cooked spaghetti. The result is that a gene's nearest
neighbors in three-dimensional space may be on completely different
chromosomes. In collaboration with the laboratories of Dr. Bill Noble, Dr.
Stan Fields, and Dr. Jay Shendure (all faculty members in the Department of
Genome Sciences), Zhijun Duan in our lab developed a method for capturing
interactions within and between chromosomes genome-wide. Mirela Andronescu
(Noble Lab) used this information to construct a three-dimensional model of
the genome of budding yeast (Duan
et al., Nature)
The information provides an entirely new
epigenetic view of the genome, and will likely provide important insights into
cell state, cell identity, cancer, and evolution. We plan to use this new
method to characterize the genomic architecture of stem cells, and to
understand how this changes during stem cell differentiation.
Three-Dimensional Model of the Yeast Genome
Duan Z, Andronescu M, Schutz K, McIlwain S, Kim YJ, Lee C, Shendure J, Fields
S, Blau CA*, Noble WS*. A
three dimensional model of the yeast genome. Nature 2010 May
20;465(7296):363-7. Epub 2010 May 2. (* denotes co-corresponding authors)
Smarter War on Cancer
are far more variable on a molecular level than they appear under the
microscope. Still, we continue to treat most cancers based on their appearance
an approach nearly as crude as giving a blood transfusion to everyone who
complains of fatigue. Today, however, emerging genomic and computational
technologies are transforming cancer research. That research, in turn,
promises to transform cancer treatment as well.
"N of 1" approach
Blau Lab is establishing the infrastructure to treat a small number of highly
motivated cancer patients as individual experiments: in scientific parlance,
an "N of 1." Vast amounts of data will be analyzed from each
patient's tumor to predict which proteins should be targeted in order to
destroy the cancer. Each patient would then receive a drug regimen tailored to
his or her tumor. In this kind of single-subject approach, there is no control
group against which to compare the response of the experimental subject.
Instead, each patient would serve as his or her own control, using a technique
called serial molecular monitoring. In this technique, the patient would
receive a drug designed to block a particular target protein. A biopsy would
then be performed to confirm whether the drug had worked and the target had
indeed been blocked. In this way, researchers would track the tumor's
molecular response to treatment through repeated biopsies (a requirement that
may eventually be replaced by sampling blood). One of the most important
advantages of serial molecular monitoring is that it would reveal strategies
that tumors adopt to evade therapy, possibly uncovering new targets of
patient-centered approach represents a dramatic departure from traditional
oncology. Because these novel patient-specific combinations of drugs could
have unforeseen side effects, the methodological, regulatory, and ethical
framework for cancer research would need to be reconsidered from the ground
up. Therapies that appear to be effective would be validated in small trials
involving other patients with similar molecular profiles. Unsuccessful
therapies could be analyzed to refine our understanding of tumor biology and
drug mechanisms. The N of 1 approach may not hit immediate home runs. However,
the extensive body of knowledge generated from each patient should, upon
aggregation with data from other patients, enable us to tell from a blood
sample which patients will respond to particular drugs. In time, we hope to be
able to stop tumors by anticipating the escape routes they are likely to take.
this approach will be very expensive for early adopters, technology costs are
falling at exponential rates (think of Moore's Law for integrated circuits).
Eventually, the approach should lead to dramatic reductions in health-care
costs. For one thing, the approach allows us to administer these expensive
drugs only to patients for whom they are most likely to work. For another, the
costs of the approach will go down and and scalability increase once
expected advances in technology allow us to use simple blood draws rather than
repeated tumor biopsies.
many significant challenges remain, the primary roadblock to implementing the
single-subject approach is financial. Will insurance companies or federal
agencies pay to test this new paradigm for cancer treatment? Will patients
with difficult-to-treat cancers (and the means to fund their own treatment) be
willing to take on this grand experiment for their own benefit,
potentially, and for the benefit of other patients? We believe that it's time
to find out.