Transcript New Proteasome inhibitors in myeloma — Dr Holger Auner

New Proteasome Inhibitors in Myeloma
Holger Auner MD PhD
Centre for Haematology
Department of Medicine
Hammersmith Hospital Campus
Imperial College London
chemistry
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cell biology
?
clinical outcomes
Nobel Prize in Chemistry 2004
"for the discovery of ubiquitin-mediated protein degradation"
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Aaron Ciechanover
Avram Hershko
Irwin Rose
*1947
*1937
1926-2015
Protein synthesis and degradation are co-ordinated to maintain proteostasis
functional proteins
Rudolf Schoenheimer, 1942
amino acids
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Protein synthesis and degradation are co-ordinated to maintain proteostasis
functional proteins
1950s to mid 70s
amino acids
Ciechanover A, Nature Reviews
Molecular Cell Biology 2005
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Cancer cells suffer from proteotoxic stress
dysfunctional proteins
amino acids
Hanahan & Weinberg, Cell 2000
Kroemer & Pouyssegur Cancer Cell 2008
Luo, Solimini & Elledge, Cell 2009
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Cancer cells highly depend on protein degradation
dysfunctional proteins
~80-90%
amino acids
Ciechanover, Nature Reviews Mol Cell Biol 2005
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The proteasome degrades most intracellular proteins
Proteasomal activity
~20%
<5%
~80%
K48 / K11
www.biomol.com
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The proteasome degrades most intracellular proteins
Immunoproteasome
(lymphoid, haematopoietic, IFNγ/TNFα)
β1i (LMP2)
β2i (MECL1)
β5i (LMP7)
K48 / K11
www.biomol.com
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The proteasome degrades most intracellular proteins
Immunoproteasome
(lymphoid, haematopoietic, IFNγ/TNFα)
β1i (LMP2)
β2i (MECL1)
β5i (LMP7)
K48 / K11
www.biomol.com
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How does proteasome inhibition kill myeloma cells ?
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[1] misfolded proteins (‘ER stress’)
- misfolded Ig ??
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protein
synthesis
protein
degradation
amino acids
Obeng & Boise et al, Blood 2006; and many others
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X
How does proteasome inhibition kill myeloma cells ?
x
[1] misfolded proteins (‘ER stress’)
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protein
synthesis
protein
degradation
[2] amino acid shortage
Vabulas & Hartl, Science 2005
Suraweera & Bertolotti et al, Mol Cell 2012
Parzych & Auner et al, Cell Death Dis 2015
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X
How does proteasome inhibition kill myeloma cells ?
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[1] misfolded proteins (‘ER stress’)
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protein
synthesis
protein
degradation
X
[3] stabilisation of pro-apoptotic molecules (Bcl-2)
[2] amino acid shortage
[4] reduced NFκB signalling
[5] impaired DNA damage response
[6] downstream activation of JNK, caspases etc
Auner & Cenci, BJH 2014
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Why are some myeloma cells (and other cancer cells) resistant to
proteasome inhibition?
Ineffective in other haematopoietic and solid malignancies with…
extensively mutated genomes
dysregulated NFκB signalling
immunoproteasome expression
Secretory/non-secretory myelomas & ‘secretory’ cancers (osteosarcoma etc)
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Why are some myeloma cells (and other cancer cells) resistant to
proteasome inhibition?
[1] The ‘Load versus Capacity ‘ model
Bianchi G, Blood 2009
Cenci S, Curr Opin Cell Biol 2011
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Why are some myeloma cells (and other cancer cells) resistant to
proteasome inhibition?
[1] The ‘Load versus Capacity ‘ model
TJP1 ↓
EGFR/JAK1/STAT3 ↓
Zhang & Orlowski et al, Cancer Cell 2016
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LMP2 and LMP7 ↓
Bortezomib-sensitivity ↑
Why are some myeloma cells (and other cancer cells) resistant to
proteasome inhibition?
[1] The ‘Load versus Capacity ‘ model
‘Proteasome bounce-back’
Proteasome
Radakrishnan & Deshaies et al, Mol Cell 2010
Radakrishnan & Deshaies et al, eLife 2014
Sha & Goldberg, Curr Biol 2014
Vangala & Radakrishnan et al, Curr Biol 2016
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Nrf1 ↑
De novo
proteasome
synthesis
Bortezomib-sensitivity ↓
Why are some myeloma cells (and other cancer cells) resistant to
proteasome inhibition?
[1] The ‘Load versus Capacity ‘ model
Xbp1s- pre-plasmablast
Leung-Hagesteijn & Tiedemann et al, Cancer Cell 2013
Chaidos & Karadimitris et al, Blood 2013
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Xbp1s+ mature plasma cell
Why are some myeloma cells (and other cancer cells) resistant to
proteasome inhibition?
[2] Alternative protein degradation pathways
Yoshinori Ohsumi
HDAC6
 hydroxychloroquine, clarythromycin, HDAC-i ?
Kaur & Debnath, Nature Reviews Mol Cell Biol 2015
Riz & Hawley et al, Oncotarget 2015
Milan & Cenci et al, Autophagy 2015
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Why are some myeloma cells (and other cancer cells) resistant to
proteasome inhibition?
[3] Inadequate proteasome inhibition
Typical whole blood lysate proteasome inhibition after one bortezomib dose
Deshaies, BMC Biology 2014
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Why are some myeloma cells (and other cancer cells) resistant to
proteasome inhibition?
[3] Inadequate proteasome inhibition
Typical whole blood lysate proteasome inhibition after one bortezomib dose
Can novel proteasome inhibitors achieve this –
and is it relevant ?
Deshaies, BMC Biology 2014
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The players
Bortezomib
boronic acid based
reversible
β5/ β5i inhibition
(chymotrypsin-like)
Ixazomib
boronic acid based
reversible
β5/ β5i inhibition
(chymotrypsin-like)
oral
Carfilzomib
epoxyketone-derived
irreversible
β5/ β5i inhibition
(chymotrypsin-like)
Oprozomib
(ONX 0912)
Marizomib
(NPI-0052)
epoxyketone-derived
irreversible
β5/ β5i inhibition
(chymotrypsin-like)
oral
β Lactone
irreversible
Pan-β inhibition
(CT, T, C-like)
Are the new proteasome inhibitors really that much different from bortezomib, clinically?
Ixazomib
Bortezomib
(1.3mg/m2,
(0.25-3.11mg/m2, day 15, blood)
day 11, blood)
Reversible; FAST off rate
(in vitro β5 dissociation half life ~18 min)
Reversible; SLOW off rate
(in vitro β5 dissociation half life ~110 min)
Carfilzomib
IRREVERSIBLE
Moreau et al, Clin Pharmacokin 2012; O’Connor & Orlowski et al, Clin Cancer Res 2009; Assouline et al, Blood Cancer
Journal 2014; Kupperman et al, Cancer Res 2010
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Ixazomib
Bortezomib
(1.3mg/m2,
(0.25-3.11mg/m2, day 15, blood)
day 11, blood)
Reversible; FAST off rate
(in vitro β5 dissociation half life ~18 min)
Reversible; SLOW off rate
(in vitro β5 dissociation half life ~110 min)
Carfilzomib
IRREVERSIBLE
Moreau et al, Clin Pharmacokin 2012; O’Connor & Orlowski et al, Clin Cancer Res 2009; Assouline et al, Blood Cancer
Journal 2014; Kupperman et al, Cancer Res 2010
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Two key studies as examples to compare BTZ, CFZ, and IXA
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Carfilzomib 56mg/m2 (20 days 1,2 cycle 1) days 1,2,8,9,15,16 + Dexamethasone (20mg) days 1,2,8,9,15,16,22,23 (n=464)
vs
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Bortezomib (1.3mg/m ) days 1,4,8,11 IV or SC + Dexamethasone (20mg) days 1,2,4,5,8,9,11,12 (n=465)
until progression
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ITT
previous Btz
no previous Btz
Longer PFS in all subgroups with CFZ
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Better CR and VGPR rates with CFZ
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Adverse events
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Dose reductions
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ENDEAVOR summary
• Superior PFS with CFZ in all subgroups
• Deeper responses with CFZ
• More SAEs with CFZ (48%) compared to BTZ (36%) but similar discontinuation rates
• Moderately different AE profile (cardiovascular vs neurological)
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Ixazomib + Lenalidomide + Dexamethasone
Ixazomib: 4 mg on days 1, 8, and 15
Lenalidomide: 25 mg* on days 1-21
Dexamethasone: 40 mg on days 1, 8, 15, 22
Randomization
N=722
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1:1
Repeat every 28 days until progression, or unacceptable
toxicity
Placebo + Lenalidomide + Dexamethasone
Placebo: on days 1, 8, and 15
Lenalidomide: 25 mg* on days 1-21
Dexamethasone: 40 mg on days 1, 8, 15, 22
Moreau, ASH 2015
Moreau, ASH 2015
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Moreau, ASH 2015
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Moreau, ASH 2015
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Moreau, ASH 2015
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Moreau, ASH 2015
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Moreau, ASH 2015
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TOURMALINE-MM1 summary
IXA when combined with Rd:
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improved PFS in high-risk and standard risk patients
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improved TTP and response rates
IXA added limited toxicity to that seen with Rd
• Low rates of PN and no cardiovascular or renal signals
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VD
KD
ID
ENDEAVOR
ENDEAVOR
(CHAMPION-1)
Kumar et al,
Blood 2016
≥VGPR
29 %
54 (47) %
27 %
PFS
9.4 mo
18.7 (12.6) mo
7.8 – 8.4 mo
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VD
KD
ID
ENDEAVOR
ENDEAVOR
(CHAMPION-1)
Kumar et al,
Blood 2016
≥VGPR
29 %
54 (47) %
27 %
PFS
9.4 mo
18.7 (12.6) mo
7.8 – 8.4 mo
VRD
KRD
IRD
Richardson et al,
Blood 2014
ASPIRE
TOURMALINE-MM1
≥VGPR
28 %
70 %
48 %
PFS
9.5 mo
26.3 mo
20.6 mo
VD
KD
ID
ENDEAVOR
ENDEAVOR
(CHAMPION-1)
Kumar et al,
Blood 2016
≥VGPR
29 %
54 (47) %
27 %
PFS
9.4 mo
18.7 (12.6) mo
7.8 – 8.4 mo
VRD
KRD
IRD
Richardson et al,
Blood 2014
ASPIRE
TOURMALINE-MM1
≥VGPR
28 %
70 %
48 %
PFS
9.5 mo
26.3 mo
20.6 mo
VCD
KCD
ICD
Kropff & DSMM
Haematol. 2007
Bringhen at al, Blood
2014 (ND elderly)
Kumar et al,
ASH 2016
CR: 16 %
71 %
16 %
12 mo
76 % 2-y PFS
≥ 12.5 mo
(57 % 1-y PFS)
≥VGPR
PFS
MUKfive
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MUKeight
Marizomib (NPI-0052) – an irreversible β5, β1 and β2 inhibitor
Mouse whole blood proteasome inhibition by
marizomib (NPI-0052) vs bortezomib at MTD
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Chauhan & Anderson et al, Cancer Cell 2005;
Marizomib (NPI-0052) – an irreversible β5, β1 and β2 inhibitor
Mouse whole blood proteasome inhibition by
marizomib (NPI-0052) vs bortezomib at MTD
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Monkey prefrontal cortex proteasome inhibition by
marizomib
Chauhan & Anderson et al, Cancer Cell 2005; Di & Botha et al, Neuro-Oncology 2016;
Marizomib (NPI-0052) – an irreversible β5, β1 and β2 inhibitor
Mouse whole blood proteasome inhibition by
marizomib (NPI-0052) vs bortezomib at MTD
Monkey prefrontal cortex proteasome inhibition by
marizomib
Leukaemia and MM patients whole blood proteasome
inhibition by marizomib
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Chauhan & Anderson et al, Cancer Cell 2005; Di & Botha et al, Neuro-Oncology 2016; Levin et al BJH; 2016
MR or PR (+Dex)
once weekly i.v
twice weekly i.v.
2/32 (6%)
4/36 (11%)
Marizomib and Oprozomib at ASH 2016
n=2
drug
diseases
ORR
author
Marizomib Pom Dex (I)
RRMM
53%
Spencer et al
Single agent oprozomib (Ib/II)
RRMM / WM
22-34% / 47-71%
Ghobrial et al
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Chauhan & Anderson et al, Cancer Cell 2005
Marizomib and Oprozomib at ASH 2016
n=2
drug
diseases
ORR
author
Marizomib Pom Dex (I)
RRMM
53%
Spencer et al
Single agent oprozomib (Ib/II)
RRMM / WM
22-34% / 47-71%
Ghobrial et al
Carfilzomib and Ixazomib at ASH 2016
n=too many to show…
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Chauhan & Anderson et al, Cancer Cell 2005
Conclusions
Novel proteasome inhibitors add to our anti-myeloma
armamentarium (oral, different AE profiles)
MsOA still very poorly understood
Biochemical / preclinical data (reversibility, dissociation rate,
subunit inhibitions) are of (very) limited value in predicting
clinical effects
 Where do we go in targeting protein degradation?
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Potential other targets linked to the UPS
X
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Potential other targets linked to the UPS
X
X
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Potential other targets linked to the UPS
X
X
VCP/p97
X
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Potential other targets linked to the UPS
X
X
VCP/p97
X
X
amino acids
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Potential other targets linked to the UPS
X
X
VCP/p97
X
X
amino acids
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X
proteasome-regulated
cellular functions
(DNA damage, metabolism,
cell cycle…)
THANK YOU !
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