ASH Clinical News ACN_4.4_FULL_ISSUE_DIGITAL | Page 7

Calendar
Advanced Practice Providers Oncology
Summit
The goal of this summit is to foster collaboration,
share best practices, and provide a forum for
peer-to-peer interaction among advanced practice
providers who are actively engaged in caring for
oncology patients. Find more info at
apponcologysummit.mededmanager.com.
ASH Meeting on Lymphoma Biology
August 2 – 5, 2018
Chantilly, VA
This meeting brings together experts from around the
world to discuss the latest lymphoma fundamental
science, address challenges in the field, establish the
highest priorities for investigation, and develop novel
therapeutics.
UPCOMING DATES AND LOCATIONS:
April 6 – 7, 2018
Dallas/Fort Worth, TX
ASH Meeting
on Hematologic
Malignancies
September 7 – 8,
2018
Chicago, IL
Top experts in hematologic
malignancies discuss the
latest developments in clinical care and provide answers
to your most challenging patient care questions in a
small-group setting. The program content is structured as
“How I Treat” presentations, which showcase each speaker’s
evidence-based treatment approaches.
Mark your calendar for the 2018 ASH
Annual Meeting ta king place
December 1-4, 2018, in
San Diego, CA.
April 20 – 21, 2018
Seattle, WA
May 4 – 5, 2018
Cleveland, OH
July 13 – 14, 2018
Philadelphia, PA
MCL-1, a BCL-2 family member, is an
August 24 – 25, 2018
San Francisco, CA
September 14 – 15, 2018
Denver, CO
American Association for Cancer
Research Annual Meeting
April 14 – 18, 2018
Chicago, IL
The annual meeting, for which the theme is “Driving In-
novative Cancer Science to Patient Care,” highlights cancer
science and medicine from international institutions.
Highlights of ASH® Latin America
April 27 – 28, 2018
Rio de Janeiro, Brazil
Oncology Nursing Society Annual
Congress
May 17 – 20, 2018
Washington, DC
The 43rd Annual Congress features the latest in
research, clinical practice, advanced practice, and lead-
ership, presented by oncology nursing professionals.
2018 American Society of Clinical
Oncology Annual Meeting
June 1 – 5, 2018
Chicago, IL
The American Society of Clinical Oncology brings to-
gether 32,000 oncology professionals from around the
world to discuss state-of-the-art treatment modalities,
new therapies, and ongoing controversies in the field.
European Hematology Association
Annual Congress
June 14 – 17, 2018
Stockholm, Sweden
The 23nd Annual Congress covers every subspecialty
in hematology with experts from around the world.
The educational and scientific program will highlight
up-to-date clinical practice and the latest findings
in hematology research.
ASH Summit on Emerging
Immunotherapies for
Hematologic Diseases
July 12 – 13, 2018
Washington, DC
ASH’s newest meeting examines pre-
clinical and clinical factors influencing
the effective development, regulation,
and implementation of immunothera-
pies for hematologic diseases.
in MCL-1–dependent AML 1-3
MCL-1 dependence may drive progression
of AML 1,2
Acute myeloid leukemia (AML) is associated with high
mortality and is challenging to treat, with an overall
5-year survival rate of 27%. 4,5 Standard therapies often fail
to achieve the goal of inducing complete remission in
25%–50% of patients, and relapse is common even in
patients who have an initial response to treatment. 1,5
Disease progression and treatment resistance in a subset *
of AML have been associated with a key anti-apoptotic
protein, myeloid cell leukemia 1 (MCL-1). 1,2 This is referred
to as MCL-1 dependence. 6 Understanding the role of
MCL-1 can inform therapeutic targeting strategies in AML. 7
Downregulation of MCL-1 to enable apoptosis
of leukemic blasts may be a rational
therapeutic strategy in MCL-1–dependent AML 7
The activity of cyclin-dependent kinase 9 (CDK9)
is essential for the transcription of MCL-1 mRNA in
leukemic blasts. 9,10
CDK9
Recruitment
of CDK9
CDK9
RNA
polymerase II
MCL-1 may have multiple roles in sustaining
AML blasts 1,3
MCL-1 is a member of the apoptosis-regulating BCL-2 family
of proteins. 8 In normal function, MCL-1 is essential for early
embryonic development and for the survival of multiple
cell lineages, including lymphocytes and hematopoietic
stem cells. 3
However, in MCL-1–dependent AML, MCL-1 has been
shown to sustain the survival of AML cells, which may lead
to relapse. 1 MCL-1 dependence is also associated with
resistance to agents that otherwise have activity against
leukemic blasts. 8
MCL-1
expression
Because of the short half-life of MCL-1 (2-4 hours),
the effects of targeting upstream pathways
are expected to reduce MCL-1 levels rapidly. 11
CDK9 inhibition has been shown to block MCL-1
transcription, resulting in the rapid downregulation
of MCL-1 protein, thus triggering apoptosis. 8,12,13
A key function of MCL-1 is to inhibit apoptosis 1
In addition, independently of its anti-apoptotic activity,
MCL-1 has a role in mitochondrial function that may
promote cancer cell survival and proliferation. 3 The anti-
apoptotic and mitochondrial functions of MCL-1 may
synergize to promote tumor progression by inhibiting
apoptosis and supporting proliferation. 3
*The prevalence of MCL-1–dependent AML is
under investigation.
A matter of cell life
and cell death
Learn more at www.toleropharma.com
Tolero Pharmaceuticals, Inc. is a leader in developing novel therapeutics to inhibit biological drivers of
hematologic and oncologic diseases by targeting pathways for gene transcription and drug resistance.
References: 1. 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. 2. 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. 3. Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions
to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29. 4. National Cancer Institute. Cancer stat facts: acute myeloid leukemia. https://seer.cancer.gov/statfacts/html/amyl.html. Accessed July 29,
2017. 5. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood. 2005;106(4):1154-1163. 6. Wei G, Margolin AA, Haery L, et al. Chemical genomics identifi es small-molecule
MCL1 repressors and BCL-xL as a predictor of MCL1 dependency. Cancer Cell. 2012;21(4):547-562. 7. Bose P, Grant S. Mcl-1 as a therapeutic target in acute myelogenous leukemia (AML). Leuk Res Rep.
2013;2(1):12-14. 8. 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. 9. 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. 10. Ocana A, Pandiella A. Targeting oncogenic
vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234. 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. 12. Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle. 2016;15(4):519-5 27. 13. Yin T, Lallena
MJ, Kreklau EL, et al. A novel CDK9 inhibitor shows potent antitumor effi cacy in preclinical hematologic tumor models. Mol Cancer Ther. 2014;13(6):1442-1456.
Tolero Pharmaceuticals is a registered trademark of Tolero Pharmaceuticals, Inc. in the US. ©2017 Boston Biomedical, Inc. All rights reserved. PM-ALV-0002 11/2017
ASHClinicalNews.org
Transcriptional control of nearby
genes, including MCL-1