ASH Clinical News ACN_4.14_Full Issue_web | Page 149

FEATURE
a disease’s genomic landscape. But not all
mutations are created equal. In MDS, Dr.
Ebert said, many of the primary drivers of
the disease discovered to date are not able
to be treated with drugs.
This isn’t a problem unique to MDS, he
noted. The many hundreds or thousands of
variations detected using whole-genome,
whole-exome, or targeted sequencing can
be beneficial, neutral, disease-associated, or
of unknown consequence to the patient.
Dr. Godley discussed testing for AML
as an example. Many physicians sending
panels to in-house or commercial labora-
tories may be testing for a wide variety of
AML-related genes, including p53, ASXL1,
PHF6, DNMT3A, TET2, and more.
“There is an entire core of molecular
genes that are prognostically significant
for AML,” Dr. Godley explained. “If you
surveyed all treating physician members
of the American Society of Hematology,
I think you would find that people are
sending out a wide range of gene panels,
and they are all interpreting the results
very differently.”
As part of its Precision Medicine
Initiative, the American Society of He-
matology (ASH) is working to enhance
genomic profiling of all hematologic
disease and has appointed dedicated task
forces and working groups to clarify how
genomic information can be used in the
treatment of blood disorders. The Somat-
ic Working Group, for one, is exploring
ways to improve and educate physicians
about the clinical application of molecu-
lar data. Read more about ASH’s efforts
in this area in SIDEBAR 2 .
“Interpretation of these results is
complicated, and I don’t think people have
a true understanding of how complicated
it is,” she added. “For example, there is
an underappreciation of how common
germline mutations in AML are. Whether
a mutation is somatic or germline is a
question that many physicians are likely
not even thinking about.”
Clonal hematopoiesis further com-
plicates the issue, Dr. Godley said. “If I
see a patient with a TP53 mutation in
the peripheral blood, I can give three
possible explanations: That patient could
have MDS, clonal hematopoiesis, or Li-
Fraumeni syndrome, which involves an
inherited mutation.”
Clinicians need more knowledge
about what genes should be included on a
panel, she noted, providing the example of
a family practitioner from Michigan who
sent samples to a large commercial lab to
test for inherited thrombocytopenia. He
didn’t know that the commercial panel
he selected didn’t include some of the
most common genes associated with the
condition.
“If the average clinician thinks a panel
is comprehensive when it isn’t – or assumes
that these large companies perform their
due diligence when they do not – that is a
huge problem,” she said.
Unleash the Data!
The lack of knowledge surrounding next-
generation sequencing interpretation
is not surprising given the explosion of
genomic information and the prevalence
of electronic health records. Combined,
these two developments have produced an
unprecedented amount of health data. The
Moonshot initiative seeks to maximize ac-
cess to these data through efforts like the
NCI’s Genomic Data Commons (GDC).
“The challenge in bringing precision
medicine to every patient is to truly
understand which genetic changes
in cancer are important drivers of
the malignant process.”
—LOUIS M. STAUDT, MD, PhD
CDK9 regulation of MCL-1
inhibits apoptosis, enabling
1-5
AML BLAST
SURVIVAL
CDK9
MCL-1 mRNA
MCL-1 dependence may
drive progression of AML
3,6
CDK9 is a key regulator of
MCL-1 function
1,2,5
Disease progression and
treatment resistance in a subset
of acute myeloid leukemia (AML)
have been associated with a key
anti-apoptotic protein, myeloid
cell leukemia 1 (MCL-1). 3,6 MCL-1
is a member of the apoptosis-
regulating BCL-2 family of proteins. 7 MCL-1 mRNA transcription in
AML blasts is regulated by cyclin-
dependent kinase 9 (CDK9), 1,2 a
protein that plays a critical role in
transcription regulation without
directly affecting cell-cycle control. 5,10
In MCL-1–dependent AML,* the
AML blasts depend primarily
on the function of MCL-1 for the
anti-apoptotic mechanism of
survival. 8,9 MCL-1 inhibits apoptosis
and sustains the survival of AML
blasts, allowing them to proliferate,
which may lead to relapse. 3 MCL-1
dependence is also associated
with resistance to agents that
otherwise have activity against
leukemic blasts. 7 CDK9-mediated transcriptional
regulation of anti-apoptotic
proteins, including MCL-1,
is critical for the survival of
MCL-1–dependent AML blasts. 5
Inhibition of CDK9 as a
rational therapeutic strategy
in MCL-1–dependent AML
1,5,7
Because MCL-1 has a short half-
life of 2-4 hours, the effects of
targeting its upstream regulators
are expected to reduce MCL-1
levels rapidly. 11 CDK9 inhibition
has been shown to block MCL-1
transcription, resulting in rapid
depletion of MCL-1 protein, which
may restore apoptosis in MCL-1–
dependent AML blasts. 1,5,7
Understanding the role of CDK9
in regulating MCL-1 may inform
therapeutic targeting strategies
in AML.
*The prevalence of MCL-1–dependent
AML is under investigation.
BOOTH
#3012
Learn more about available
clinical trials at the 2018
ASH Annual Meeting
A matter of cell life
and cell death
Learn more at www.toleropharma.com
Tolero Pharmaceuticals, Inc. is a leading developer of novel therapeutics to inhibit
biological drivers of hematologic and oncologic diseases.
References: 1. Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by fl avopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106(7):2513-2519. 2. Ocana A, Pandiella A.
Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234. 3. Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1
is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120-125. 4. Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer
biology. Trends Cell Biol. 2013;23(1):22-29. 5. Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A. Cyclin dependent kinase 9 inhibitors for cancer therapy. J Med Chem. 2016;59(19):8667-
8684. 6. Xiang Z, Luo H, Payton JE, et al. Mcl1 haploinsuffi ciency protects mice from Myc-induced acute myeloid leukemia. J Clin Invest. 2010;120(6):2109-2118. 7. Thomas D, Powell JA, Vergez F, et al. Targeting
acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748. 8. Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, et al. FLT3-ITD up-regulates
MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD–specifi c STAT5 activation. Blood. 2009;114(24):5034-5043. 9. Butterworth M, Pettitt A, Varadarajan S, Cohen GM. BH3 profi ling
and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells. Br J Cancer. 2016;114(6):638-641. 10. Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle.
2016;15(4):519-527. 11. Gores GJ, Kaufmann SH. Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors. Genes Dev. 2012;26(4):305-311.
Tolero Pharmaceuticals is a registered trademark of Sumitomo Dainippon Pharma Co., Ltd. ©2018 Boston Biomedical, Inc. All rights reserved. PM-NPS-0023 10/2018
ASHClinicalNews.org