Ohio State's 2016 ASH Review Blood and Marrow Trasplantation (with Turning Po...OSUCCC - James
Ohio State’s 2016 ASH Review
Blood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
Ohio State's 2016 ASH Review Blood and Marrow Trasplantation (with Turning Po...OSUCCC - James
Ohio State’s 2016 ASH Review
Blood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
Her2Neu positive breast cancer is comprises of about 15-20% of all breast cancer. Among them quite a few number of patients present as de novo metastasis . In this presentation you ll find a guide how to manage it with relevant evidences. Presentation is meant for Oncology trainees.
Report Back from San Antonio Breast Cancer Symposium (SABCS 2022)bkling
Curious about the latest developments in Early-Stage Breast Cancer and Metastatic Breast Cancer Research? Join us as Dr. Anne Blaes, the Division Director of Hematology/Oncology/Transplantation and Professor in Hematology/Oncology at the University of Minnesota, breaks down the most recent developments released at the annual San Antonio Breast Cancer Symposium regarding early-stage and metastatic breast cancer research.
Synthetic Fiber Construction in lab .pptxPavel ( NSTU)
Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
A Strategic Approach: GenAI in EducationPeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
Antifertility, Toxicity studies as per OECD guidelines
Acetabularia Information For Class 9 .docxvaibhavrinwa19
Acetabularia acetabulum is a single-celled green alga that in its vegetative state is morphologically differentiated into a basal rhizoid and an axially elongated stalk, which bears whorls of branching hairs. The single diploid nucleus resides in the rhizoid.
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
Is it time to consider targeted therapy in combination for newly diagnosed AML?
1. STEVEN M KORNBLAU, MD
Houston, USA
• Professor of Medicine, UT MD Anderson Cancer Center
• He was a fellow in Hematology and Oncology at the MD
Anderson Cancer Center from 1988 through 1991 and also
completed six months of training at the Royal Free Hospital
in London, after which he joined the faculty at MD
Anderson in 1991 and became a full professor in 2007. He
holds a dual position in the department of leukemia and the
department of stem cell transplantation and cellular
therapy. Dr. Kornblau’s laboratory research focuses on
protein expression patterns in hematological malignancies.
Additionally, he runs the Leukemia Sample Bank at MDACC,
one of the largest leukemia and myeloma tissue
repositories in the world..
2. Is it time to consider targeted
therapy in combination for
newly diagnosed AML?
Steven M. Kornblau, M.D.
Department of Leukemia
Department of Stem Cell Transplantation and
Cellular Therapy
3. When you say targeted,
which type of target?
• Clinical features
– Age
– PS
– Gender
• Molecular features ?
Covered by
other
lectures
Covered in
this lecture
4. Many Molecular Targets,
Which do you Mean?
• Mutation
• Methylation: Epigenetics
• MicroRNA
• mRNA
• Microenvironment
• Modus Operandi/Mechanistic: Proteins
• IMmunity
5. When Might Targeted Therapy be Indicated?
You have identified a target that:
• Divides the population into discrete groups
– Haves & Have nots
• A reproducible standardized assay exists
– so grouping patients is possible
• An agent that targets the target exists
• Responses in vitro are better (restricted to?)
the population with the target
6. When Is Combined Targeted Therapy Indicated?
• Targets with available agents exist
• Targets occur together simultaneously
– Not mutually exclusive like IDH1 & Tet2
• There is a rationale for combining therapy against both
targets simultaneously
– Non overlapping pathways targeting 2 key functions
– Within the same pathway or function
• Like Bactrim for bacteria
– Combination additive or synergistic & preliminary data
supports use
• Both agents are available to combine
– Licensed so can have investigator initiated trial
– Companies agree to work together
7. What about combining targeted
therapy with non targeted therapy?
• Many targeted therapies in development
• Individual use often disappointing
• Decades of experience with “non-targeted”
traditional chemotherapy
• Maybe “targeted” agents would be more
effective if combined with “traditional”
chemotherapy ?
8. The BIG Caveat
• In 2015, almost none of these agents
are FDA approved
• Can only use them in a clinical trial
• Therefore cannot combine them with
existing chemotherapy, or each
other.
14. Common Mutations & Available Agents
Mutation Incidence Prognostic Drugs in
Development ?
All Diploid
NPM1 25-35% 45-60% Favorable
(FLT3 WT)
No
FLT3 ~20% 28-34% ITD: Adverse
D835 ?
Multiple in trial
DNMT3a 18-22% 30-37% Unclear No, but…
IDH1 & IDH2 15-20% 25-30% Adverse ? 2 in trial, others
in development
ASXL1 5-11% 5-12% Adverse No
TET2 ~13 % 9-23% Adverse ? No
RUNX1 5-15% 8-16% Adverse No
16. FLT3 Inhibitors Under Development
Preclinical Phase I Phase II Phase III
VX-322 IMC-EB10 Sorafenib Lestaurtinib
VX-398 KW-2449 MLN-518 Midostaurin
MC-2002 Ponatinib Crenolanib Quizartinib
MC-2006 CHIR-258 PLX3397
ASP2215
None are mutation specific – So really targeted?
The only FDA approved
FLT3 inhibitor….
….but not approved for this
indication
17. FLT3 inhibitors
• As single agents very few CRs
– Better at reducing PB than BM blasts
• Will addition to Chemotherapy improve results ?
ALL FLT3 mut Chemo Chemo + L
N 112 112
Age 54 (21-79) 59 (20-81)
CR 12% 17%
CRp 9% 9%
CR1 <6 11% 19%
CR1 >6 29% 32%
Survival 160D 160D
CR1 <6mo MEC + Lestaurtinib 80mg
CR1 >6 mo HiDAC + Lestaurtinib 80mg
Response correlates with target level inhibitio
Only 58% got inhibited at D 15
Levis Blood 2011:117;3294-3301
FLT3 Mut FLT3 WT
Dose 50 100 50 100
N 18 17 31 29
Age>64 39% 53% 77% 72%
CR 0 0 0 0
PR 0 1 0 0
Heme
improvement
50% 41% 43% 26%
Midostaurin 50 or 100 mg twice daily
Fischer JCO 2010:28;4239-45
No evidence of FLT3 –ITD targeting Barely better than chemo alone
18. AC220-002 (Quizartinib)
Phase II in AML salvage
Cohort >60, CR1 < 1 yr or 1oRef >18 Rel/Ref to 2nd line or HSCT
Mutation Status ITD+ FLT3-WT ITD+ FLT3-WT
N 92 41 99 38
Age 70 (54-85) 69 (60-78) 50 (19-77) 55 (30-73)
CR composite 54% 32% 44% (4% CR) 34% (3% CR)
PR 18% 9% 24% 13%
Median CRc
duration
12.7 wks 22.1 wks 11.3 5
Median Survival 25 19 23.1 25.6
Cortes ASH 2012 Abstract # 48
Dose: Females 90 mg Males 135 mg continuously
QTc 25 % Grade 3-4 13% 26% Gr 3-4 10%
Levis ASH 2012 Abstract # 673
19. Quizartinib+AZA or LDAC in FLT3-positive AML
• 33 pts
– 12 in phase 1; 21 in phase
2
– Rx with quizartinib 60-90
mg orally daily and AZA or
LDAC
• 63% responded:
– CR 9%, CRp 15%, CRi 36%,
– PR 3%
• 22 with FLT3-ITD: ORR
82%
Borthakur. Blood 124: abst 388; 2014
Survival
0 2 4 6 8 10 12 14
Months
0.0
0.2
0.4
0.6
0.8
1.0
SurvivalProbability
Quizartinib+ Total Died Median
Azacitidine 24 6 NR
LD Ara-C 9 5 8.2 mo
p = 0.24
• Median Overall Survival = not reached
• Alive at 6 months= 22 (66%)
20. Improved Outcome (?) of FLT3-mutated AML
Badar. Blood 124: abst 949; 2014
Pre FLT3 Agents
FLT3 Agents
20%
8 %
So maybe FLT3 patients are doing a bit better with
targeted therapy
21. So What about FLT3 combinations?
• FLT3i + chemotherapy ?
– 1st Generation +High Does MEC/HiD ara-C
• no definite improvement
– 2nd Generation +Low dose LDAC
• hints at improvement
• FLT3i + other targets
– Not tested yet
• FLT3i + Demethylators/HDACi
– Mutations often co-occur
– Not tested yet
– In vitro MS-275(entinostat)
induces growth arrest
Patel NEJM 2012;366:1079-89.
22. FLT3 Inhibition- Ready to be a “dynamic duo”?
• Target Identified ?
• Standardized Tests ?
• Drugs available ?
• Drugs show single
agent efficacy?
• Response better in
target population?
• Synergy with other
agents in vitro or
trials?
Yes
Yes
Yes – Sorafenib
Sort of
Not really
Yes for synergy
Jury out on efficacy
24. IDH in Leukemia
• IDH mutations occur in ~ 20% of AML
– frequency: 6-16% IDH1 & 8-18% IDH2
– Majority (85%) with diploid or +8
cytogenetics
– ↑ prevalence with ↑ patient age
– Strongly associate with NPM1+ and
MPN-derived AML (21-31%)
– Mutated residues occur in
conserved active site
• IDH1-R132, IDH2-R172 or -R140
• GAIN of Function
– Founder mutations, not progression
• 0/225 pts WT IDH at dx develop
IDH mutation during f/u
Dang L. Trends in Mol Med, 2010 Chou et al, Leukemia 2011
Patel NEJM 2012;366:1079-89.
25. Drugs Targeting IDH
• IDH1 = AG 120 IDH2 = AG 221
73 pts R140 =54 R172= 13
Rel Ref 55 MDS 6 New 5 CMML 5
Prior BMT 18%
Daily or BID. 30mg to 150 BID, 200mg/D
Responses in 25 / 45 = 56%: 8
CR =6 CRp =5 mCR=1 Cri=5 PR = 10
No clear dose response
Duration: 90% > 3 months
Toxicities: LFTs
Stein. ASH 2014 # 115
14 pts
100 mg BID, 3,5,800/D
Responses in 7/ 14 = 50%: 8
CR =4 mCR=2 PR = 1 SD = 6
No clear dose response
Duration: ?
Toxicities: ?
P a t ie n t 2 P a t ie n t 3 P a t ie n t 4 P a t ie n t 8
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
1 1 0
2-HGrelativetountreated(%)
U n tr e a t e d
D M S O
0 . 5 M A G - 1 2 0
1 M A G - 1 2 0
5 M A G - 1 2 0
EORTC-NCI-AACR 2014 & Hansen ASH 2014 #3734
26. IDH Inhibition- Will they pair famously
with other targeted therapies?
• Target Identified ?
• Standardized Tests ?
• Drugs available ?
• Drugs show single
agent efficacy?
• Response better in
target population?
• Synergy with other
agents in vitro or
trials?
Yes
Yes
YES & NO – Phase 1-II trials
YES!
Unknown, no WT treated
in vitro data says yes
Not tested yet.
Reason to be excited- Yes!
29. Epigenetic Regulation Single Agent Trials
DNA Methylation Histone Acetylation
• Two clinically available agents
• Azacitadine
• Decitabine
• Trials mostly AML
• Activity seen
• Demethylation seen
• In general single agent responses have
been modest
• Trials a mix of MDS & AML
• Valproic Acid ( usually + ATRA)
• Response rate 5-30% “Heme
improvement”
• Responses in low risk MDS, normal
blast %
• Vorinostat
• 2 trials as a single agent 78 patients
• Response 4.5 (1 CR) & 17% (2 Cr 2
Cri 3 HI)
• MGCD0103 29 patients, 10% 3 mCRs
• Entinostat N= 39 RR= 0%
• All induce histone deacetylation
• Correlation of response with baseline
histone acetylation ?
Dec Aza
CR 17%1
24%2
26%3
40%4
17%6
33% +
CRp 23%7
Survival
Advantage
Yes5 Yes6
1. Kantarjian JCO 2012:30;2670
2. Lubbert, Hematologica
2012:97
3. Cashen JCO 2010:28:556
4. Ritchie LeuLym 2013:54;2003
5. Eisai FDA submission 5-10-14
6. Feneaux JCO 2010:28;562
7. Thepot AmJH 2014:89;410
30. • Unfortunately nearly no data in AML
• 7 Gene Epigenetic profile predict overall response to “therapy”,
but to demethylating ? Marcucci JCO 2014:32:548-556
• No association baseline methylation or demethylation & response
• To Aza Valproic Soriano Blood 2007:110;2302-8
• To 5-aza+entinostat Fandy Blood 2009:114;2764-73
• DNMT3a correlate with response to Decitabine- Metzler leukemia 2012:26,1106
• Data from MDS suggests maybe so, or maybe not….
• TET2 mutant 82% response vs 45% (p=0.007) to AZA in MDS, low blast %
AML Izakson Leukemia (2011) 25, 1147–1152
• TET2 (ASXL1-WT) Highest response rate in MDS treated with
hypomethylating Bejar Blood. Oct 23, 2014; 124(17): 2705–2712
• Higher levels of miR-29b were associated with clinical response (P = 0.02) to
decitabine x 10D in AML Blum PNAS 2010 107:7473-78
• Baseline methylation not predictive of response to decitabine. Shen JCO
2010:28;605-13
Does Baseline Methylation or Having a Epigenetic Regulator
Mutation Confer Sensitivity to Demethylating agents in AML?
31. Bejar Blood. Oct 23, 2014; 124(17): 2705–2712
Absolutely no details on whether these patient were treated,
or what they were treated with was mentioned in the manuscript or supplemental materials
A mixture of Epigenetic modifiers and standard per Dr. G-GM
Some (% ??)
got
demethylating
agents?
32. Traina et al. Leukemia 2014:28;78-87 & ASH 2011 Abstract #461
Methylation and Histone Modifying Gene Mutations and response to
Demethylating agents in MDS
Individual Mutations Combined Mutations
33. 5’…CpG….
…GpC….5’
5’…MECpG….
…GpCME….5’
DNMT3a
DNMT1
HDAC
AC essible
De nied
AC cess
IDH1/2 2-HG
Jumongi
Bromo
domain
K4-ME
K79
MLL
K27-ME
K79
Set
EZH2
LSD1
JMJD3
HAT AC
miRNA
29-b
SP1
AG120
AG221
Bromo I
GSK525762
DOT1L (h3k29)
HDACi
Valproic
Vorinostat
Panobinostat
Demethylating
Vidaza
Dac
Tet2
Asxl1
Drugs Affecting Genes Mutated in AML
Would combined therapy
against different points work?
34. Epigenetic Regulators + Standard Chemotherapy?
Regimen Phase Dose & Schedule New or Relapsed refractory
A = Azacitidine
B = Bortezemib
BR = Brentuximab
C = cyatarabine
CL = Clorarabine
D = Decitabine
DA = Daunorubicine
E = Etoposide
EN= Entinostat
ER = Erismodegib
GO = Gemtuzumab ozogamicin
HI = Hedgehog inhibitor
I = Idarubicin
L = Lenalidomide
M = Mitoxantrone
MD = Midostaurin
P = Panobinostat
PR = Pracinostat
R = Rigosertib
RA = Rapamycin
RBV = Ribavirin
S = Selinexor
SI = Sirolimus
SO = Sorafenib
T = Temozolomide
V = Vosaroxin
VA = Valproic Acid
VO = Volasertib
VOR = Vorinostat
No shortage of combinations in trial…
Demethylating agent + ?
Roboz ASH 2014 Educational book , P44
Histone Methyltransferase +
Demethylator + HDAC
35. Vorinostat + IA
• Does adding Histone deacetylase inhibitor improve response?
– Vorinostat 600 mg t.i.d. Days 1 2 3
– Ida 12mg/m2 /d x 3 Days 4 5 6
– ara-C 1.5 g/m2 /d x 3 or 4 Days 4 5 6 (7)
• N= 75 newly diagnosed
• median age 52 (19-65)
• Cytogenetics
– 29 diploid
– FLT3-ITD =11
• Mortality 4%
• CR = 76% (n=56) including 100% in FLT3 53% in -5 -7
• Relapse in 27
• OS median all patients =82 weeks FLT3-ITD 91 weeks
• Toxicity “ no excess” w.r.t. standard IA, Skin 38%
Garcia-Manero JCO 2012;30:2204-10
Alas….
No data on
whether
methylation
status
correlates with
response
36. Epigenetic Regulators + Targeted?
An Irresistible Combination?
• Target Identified ?
• Standardized Tests ?
• Drugs available ?
• Drugs show single
agent efficacy?
• Response better in
target population?
• Synergy with other
agents in vitro or
trials?
Yes
No, which target matters?
Yes
Yes
Data equivocal
Many trials underway
Efficacy?
Targeting?
Prognosticators?
37. If you can’t target the
mutation can you target
something else?
38. A Finite Number of Mutations in AML
A Near Infinite # of Combinations
TCGA NEJM 2013
TCGA Identified
~ 23 common
mutations
How do you figure out which to target?
40. Apoptosis
Regulation
Pathway map from Cell Signaling
Agent/Co Mechanism P
h
Oblimerson
Genasense
Genta
BCL2
AS
III
AT-101
Gossypol
Ascenta
BH3 mimetic II
Obatoclax
Teva
BH3 mimetic II
Navitoclax
ABT-263
Abbvie
BH3 mimetic II
ABT-199
Abbvie
BH3 mimetic I/
II
LY2181308
ISIS
Survivin AS II
LCL-161 Smac mimetic I
Birinapent Smac mimetic
41. Venetoclax (ABT199) in AML
• Venetoclax 20-800 mg orally daily
• 32 pt with refractory AML Rx; 11 with
IDH mutations
• ORR 6/32 = 19% (2CR, 4 marrow CR)
• IDH mutations may be more sensitive:
4 responses/11 = 36%
Konopleva. Blood 124: abst 118; 2014
43. Signal Transduction
If it is on here, then it is a “target” and someone is developing
a drug against it.
Pathway maps from Cell Signaling
PI3K-AKT Ras-Raf-Mek-Erk
44. RG7388 (MDM2 antagonist) in AML
• RG7388 single-agent 400-1600 mg /D x 5 Q mo
(n=20), then extension in unRx (n=9), then in
combo with ara-C (n=23+34)
Regimen No. Rx No. Response (%)
RG single 20 2 CR, 3 CRi/MLFS (25)
RG single unRx 9 1 CRi (11)
RG+ara-C 23 6 CR + 2 PR (35)
RG+ara-C 34 4 CR+1 CRi/MLFS+1 PR (18)
Yee. Blood 124: abst 116; 2014
45. MDM2 inhibition: RG7112 + ara-C
Yee ASH 2013 Abstract # 498
Arm A N=16 Median age 70 Arm B N=27 Median age 50
Who Unsuitable for standard (re)
induction
Relapsed refractory
Regimen RG7112 + Ara-C 20 mg/M2 sc x 10D RG7112 x 5 D + ara-C 1g/M2 iv x 6 D
Response
CR 3 all P53 WT 2Cr 1 Cri 1 CRp all P53 WT
PR 0 1
SD 3 7 P53 mutated in 1
PD 8 P53 mutated in 3 11 P53 mutated in 1
Deaths 2 ARDS, Sepsis 2 sepsis
MTD 1000 mg bid x 10 D 1500 mg bid x 5 D
Functional P53 likely required
CR1 duration?
Cytogenetics?
47. NO
• But not because we don’t want to.
• Availability of agents outside of Phase I-II trials
is the limiting factor
• In the not too distant future there may be a
lot of targeted agents worth combining
Is it time to consider targeted
therapy in combination for
newly diagnosed AML?
48. Conclusions
• Tons of Targets
• Many agents in development
– Not licensed yet
• Selectivity for population bearing target not always
clear
• Improved responses in target population generally
not demonstrated
• Need a rational way to test combinations (when
targeted agents become available)
• Need reliable means to match patients & targets
• We are not there yet….
LCL161-regulated signaling pathways are shown. LCL161 antagonizes X-chromosome–linked inhibitor of apoptosis (XIAP), thereby promoting caspase activation and apoptosis. In addition, LCL161 binds to cellular IAP (cIAP) proteins, thereby enhancing their E3 ligase activity, autoubiquitination, and proteasomal degradation, which in turn leads to activation of noncanonical nuclear factor kappa B (NF-κB) signaling, upregulation of inflammatory cytokines such as tumor necrosis factor α (TNFα), and TNFα-mediated apoptosis. However, the LCL161-stimulated increase in cytokines may turn out to be a double-edge sword, because it is not only required for LCL161-induced apoptosis, but it is also responsible for toxic adverse effects such as cytokine release syndrome (CRS). FADD, Fas-associated protein with death domain; NIK, NF-κB–inducing kinase; RIP1, receptor-interacting protein 1; TNFR1, TNF receptor 1.
