indicare quale tra queste affermazioni riguardante gli inibitori di parp è sbagliata: 1.olaparib ha...
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Indicare quale tra queste affermazioni riguardante gli inibitori di PARP è SBAGLIATA:
1.Olaparib ha mostrato attività antitumorale in monoterapia nei tumori con mutazioni di BRCA1 o BRCA2
2.Potenziano l’attività antitumorale della temozolomide inibendo il sistema di riparo per escissione delle basi
3.Potenziano l’attività antitumorale dei derivati delle camptotecine, che inibiscono la Topoisomerasi 1, rendendo più lento il processo di riparo del DNA
4.La maggior parte degli inibitori di PARP compete con il NAD per il legame al sito catalitico dell’enzima
5.Potenziano l’attività antitumorale di trastuzumab (anticorpo monoclonale anti-HER2) nei tumori della mammella triple negative
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Indicare quale tra queste affermazioni riguardante gli inibitori di PARP è SBAGLIATA:
1.L’Iniparib è un inibitore di PARP irreversibile, non competitivo
2.La mancata formazione di foci di RAD51 nel tumore in seguito a trattamento con inibitore di PARP potrebbe rappresentare un fattore predittivo di risposta al farmaco
3.I tumori ovarici associati a mutazioni di BRCA1 o BRCA2 e sensibili ai composti del platino sono in genere più sensibili agli inibitori di PARP rispetto ai tumori refrattari al platino (cioè che vanno in progressione durante la terapia con composti del platino)
4.Olaparib, un inibitore di PARP che supera la barriera emato-encefalica, in studi di fase II è stato associato a carboplatino e gemcitabina per il trattamento del glioblastoma multiforme
5.La resistenza agli inibitori di PARP può essere dovuta a nuove mutazioni di BRCA1 o BRCA2, che ripristinano l’espressione della normale proteina corrispondente, o ad elevata espressione di pompe di efflusso della famiglia della Multi Drug Resistance
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PARP INHIBITORS FOR CANCER THERAPYGrazia Graziani
University of Rome “Tor Vergata”
-Involvement of PARPs in DNA repair-Rationale for using PARP inhibitors as
- chemosensitizers and radiosensitizers- in monotherapy for BRCA defective tumors
-Clinical Trials with PARP inhibitors-Challenging tasks
POLY (ADP-ribose) polymerase (PARP)
1. Nicotinamide
2. Adenine
NAD and ADP-ribose
Nicotinamide
Binding of NADBinding of NAD++
to PARPto PARPNicotinamide leavesNicotinamide leaves
Capture by oxigen fromCapture by oxigen fromGlu and Lys of acceptor Glu and Lys of acceptor
proteins proteins
PARP
NAD+
Linkage inlinear pADPr
Linkage atbranch point
Acceptorprotein
BIOLOGICAL EFFECTS DERIVING FROM PARP BIOLOGICAL EFFECTS DERIVING FROM PARP ACTIVATIONACTIVATION
• Covalent poly(ADP-ribosyl)ation influences the function of target proteins
• Interaction of ADP-ribose polymers bound to activated PARP with polymer-binding consensus motif of partner proteins
• PAR oligomers, when cleaved from poly(ADPribosyl)ated proteins, confer distinct cellular effects
• Lowering of the cellular level of its substrate, NAD+
PARP Protein
Protein
PARP
NAD+
DNA damageand repair
Cell deathpathways
Transcription
Mitoticapparatusfunction
Genomemaintenance
Aging
Inflammatoryresponses
Poly (ADP-ribose)polymerase (PARP)
PARP FAMILY MEMBERS
Hakmé et al., EMBO reports 9, 1094; 2008
PARP-1 and PARP-2 are the only PARP activated by DNA breaks
NAD binding
PARP-1PARP-2
Histone H1Histone H2B
Chromatinrelaxation at DNA breaks
DNA repair
Genomic stabilityCell survival
Recruitment and regulation of DNA repair components
at DNA breaks
DNA damage signaling
INVOLVEMENT OF PARP IN DNA REPAIR
Signaling to downstream
effectors
Cell cycle arrestBACKGROUND ON PARP’S AND DNA REPAIR
ExtensiveDNA damage
PARP-1 overactivation
Glycolysisfailure
ATPdepletion
Necrosis
ELEVATED DNA DAMAGE INDUCES PARP-1 OVERACTIVATION AND CELL DEATH
The Yin-yang of PARP activation
PARP INHIBITORS AS CHEMO- AND RADIOSENSITIZERS
Methylating agents: TEMOZOLOMIDE
Topoisomerase I inhibitors
Ionizing radiation
INHIBITION OF DNA REPAIR
Blood Brain Barrier
Spontaneous decomposition
DACARBAZINE TEMOZOLOMIDE
MethylTriazene Imidazol Carboxamide (MTIC)
Metabolicactivation
P-450
DNA damage
70% N7-Methyl-Guanine9% N3-Methyl-Adenine
Base Excision Repair (BER)
O6-Methyl-guanine-DNA methylransferase
(MGMT)
5% O6-Methyl-Guanine
SHS-CH3
TEMOZOLOMIDE and DNA METHYLATION
THE CYTOTOXICITY OF TEMOZOLOMIDE IS DUE TO O6-METHYLGUANINE
Cytotoxicity requires:– Low levels of O6-methylguanine DNA
methyltrasferase (MGMT)
– A functional Mismatch Repair (MMR)
OO66-METHYLGUANINE TOXICITY-METHYLGUANINE TOXICITYREQUIRES INTACT MISMATCH REPAIR (MMR)REQUIRES INTACT MISMATCH REPAIR (MMR)
Futile Cycle Theory
MMR cannot find a correct base complementary to O6-Methyl-GUANINE:
•Block of replication
•Single and Double strand breaks
TEMOZOLOMIDE
O6-MeG
N3-MeAN7-MeG
PARP INHIBITOR
PARP-1 and 2Base Excision Repair
(BER)
High O6-Methylguanine-DNA methyltransferase
SH
S-Me
Tumor cellsurvival
DNA repair
Tumor cell death
Defective Mismatch Repair
or
Removal of O6-methylguanine
Lack of O6-MeG toxicity
Interruption of BERpathway
N3-MeA
N7-MeG
O6-MeG
RESISTANCE TO TEMOZOLOMIDE
PARP INHIBITOR ENHANCES THE EFFICACY OF THEMETHYLATING AGENT TEMOZOLOMIDE
PARP AND REPAIR OF N-METHYLATED PURINES AND SINGLE STRAND BREAKS BY BASE EXCISION REPAIR (BER)
PARP
Short patch(1 nucleotide)
Long patch(2-15 nucleotides)
PARP
PARPXRCC1PARP
Removal of damaged baseby glycosylase
p24
p24
Strand interruption by AP endonuclease
End processing
Ligation
Gap filling
INDIRECT SINGLE STRAND BREAK
DIRECT SINGLE STRAND BREAK
PARP binds to strand break
PARP binds to strand break
IONIZINGRADIATION
METHYLATING AGENTS(N3-MethylAdenine,N7-MethylGuanine)
PARPINHIBITION
PARPINHIBITION
PERSISTANCE OF STRAND BREAKS
APOPTOSISCELL GROWTH
ARREST
PARP inhibition enhances DNA damage inducedby topoisomerase I inhibitors
Fast repair
+ PARP inhibitors Active PARP
Slow repairDNA damage
CancerCell death
Cell survival
PARP Topo I
Topo IInhibitor
Y
bind
ing
cleavage ligat
ion
rele
ase
Ybi
ndin
g
cleavage ligat
ion
rele
ase
PARP-1
Poly (ADP-ribose) accelerates ligation
Topoisomerase I inhibitor stabilizes cleavage complex
and inhibits ligation
Topoisomerase I Topoisomerase I
PARP inhibitors and topoisomerase I inhibitors
(Irinotecan and Topotecan)
Chronic inflammation
AP-1 HIF-1
PROLIFERATION OFINFLAMMATORY CELLS
INDUCTION OFANGIOGENESIS
INCREASEDANGIOGENESIS
INCREASED TUMOR GROWTH
ACTIVATION OF PARP
PARP INHIBITOR
NF-B
Tentor et al., Eur J Cancer. 2007, 43:2124
PARP inhibitors as anti-angiogenic agents
PARP INHIBITORS AS MONOTHERAPY
ANTI-TUMOR ACTIVITY IN TUMOR CELLS WITH DEFECTIVE REPAIR OF DNA DOUBLE STRAND BREAKS BY HOMOLOGOUS RECOMBINATION DUE TO BRCA MUTATIONS: THE CONCEPT OF “SYNTHETIC LETHALITY” Bryant et al. Nature 2005, 434:913.; Farmer et al., Nature 2005, 434:917
SYNTHETIC LETHALITY
• Two genes are synthetically lethal if loss of function of either gene alone is compatible with cell survival, but inactivation of both cause cell death.
• A cancer-related mutated gene can sensitise tumour cells to a drug that specifically inhibits its “synthetic lethal partner”. The same drug should not affect normal cells, thus allowing higher therapeutic selectivity
Ferrari E. et al., Eur J Cancer 46, 2889-95, 2010Modified by Fong et al. NEJM 2009 361: 123
BRCA
• The mutation increases the risk of ovarian cancer up to 60% (BRCA1 60%, BRCA2 10-20%) and breast cancer up to 84% (BRCA1 84%, BRCA2 60-80%).
• BRCA2, however, contributes less to the risk of ovarian cancer, but more to the risk of male breast cancer and pancreatic cancer.
• Only 5% of breast cancers and 10% of ovarian cancers are associated with a known genetic mutation.
• Loss of the second allele will lead to a cell not capable of the repair of DNA double strand breaks.
Homologous Recombination relies on the presence of an intact sister chromatid to act as template for correct repair of the break without loss of
sequence information
• DSB is recognized by the MRN complex (Mre11–Rad50–Nbs1), that keeps the DNA ends in close proximity to each other and is required for end resection to generate the long 3’-ssDNA overhangs required for HR.
• BRCA1, BRCA2 and BARD1 allow recruitment of the Rad51 protein which coats the ssDNA segment displacing RPA and forming a RAD51 nucleoprotein filament.
• RAD51 nucleoprotein filament catalyzes strand invasion and initiates the homology search on the intact sister chromatid.
WHY DO PARP INHIBITORS SPARE NORMAL CELLS?
Normal Cells: BRCA+/+ or BRCA +/- (heterozygous mutation)
Spontaneous Oxidative DNA damage:
Single-Strand Breaks(104/cell/day)
Base excision
+ PARP INHIBITORBase excision Repair (PARP-1): repair of
Single Strand Breaks (SSB)
Generation ofDouble Strand Breaks
(DSB)
Collapsed replication fork
Homologous Recombination
error-free repair
Repair of Double Strand Breaks (DSB)
SSB
DSB
CELL SURVIVAL
WHY DO PARP INHIBITORS SELECTIVELY KILL TUMOR CELLS WITH MUTATEDBRCA AND DEFECT IN THE REPAIR OF DNA DOUBLE STRAND BREAKS?
TUMOR cells: BRCA-/- (homozygous mutation)
Base excision
+ PARP INHIBITOR Base excision Repair (PARP-1): repair of
Single Strand Breaks (SSB
Generation ofDouble Strand Breaks
(DSB)
Collapsed replication fork
Homologous Recombination
error-free repair
PERSISTANCE of Double Strand Breaks (DSB)
SSB
DSB
DSBCELL DEATH
Spontaneous Oxidative DNA damage:
Single-Strand Breaks(104/cell/day)
Lack of PARP-mediated BER is a synthetic lethal partner of complete BRCA1 or BRCA2 functional
loss
Iglehart JD and Silver DP The New England Journal of Medicine 3612:189, 2009
RATIONALE FOR USING PARP INHIBITORS IN MONOTHERAPY IN BRCA ASSOCIATED
OVARIAN OR BREAST CANCER
SPORADIC TUMOURS WITH BRCA-LIKE CLINICAL PROPERTIES:
TRIPLE NEGATIVE BREAST CANCERS
• 15% of breast cancers
• The overlap of BRCA1-associated breast cancers with the TNBC phenotype is significant.
• There is a clinical and pathological likeness between TRIPLE NEGATIVE, BASAL-LIKE breast cancers and hereditary BRCA1 breast cancers
BASAL-LIKE AND TRIPLE NEGATIVE BREAST CANCER
• 75% triple negative breast cancers are also basal-like
• 80-90% of hereditary BRCA1 breast carcinoma have features similar to basal-like tumors
• HER2 OVEREXPRESSING and BASAL-LIKE have the worst prognosis
• Basal-like tumors are mitotically active, high-grade, invasive, and associated with younger age
• The basal-like phenotype is ER, PR and HER2-negative, and either EGFR or CK 5/6 positive
Basal-like
Her++ Normal-like Luminal
Perou CM , Nature 406: 747, 2000
Possible mechanisms of developing BRCAness in sporadic cancers
1. Increased expression of proteins that inactivate BRCA1 (ID4)
2. BRCA1 promoter methylation (10-15% sporadic breast cancers and 5-30% sporadic ovarian cancers)
3. FANCF promoter methylation4. Defects in other Fanconi’s
anemia complex proteins5. Decreased expression of
other proteins involved in HR, including Rad51, ATM
6. PTEN deficiency
Curr Probl Cancer 35:7, 2011
PARP INHIBITION BY NICOTINAMIDE PARP INHIBITION BY NICOTINAMIDE ANALOGUESANALOGUES
ONH2 N
Nicotinamide PARP inhibitor
CATALYTIC DOMAIN
O
X
H
NN
NAD+ binding
X
PARP inhibitors and clinical trials
PARP INHIBITORS
Iniparib
VeliparibOlaparib
AG014699
Nicotinamide
PARP INHIBITORS IN CLINICAL TRIALSAgent Company Route of
administrationPhase
Olaparib(PARP-1/2 IC50<2 nM)
Astra Zeneca oral I-II-III
VeliparibPARP-1/2 IC50 5 nM
Abbott Oral (BBB) I-II
Iniparib(PARP-1 M range)
BiPar/Sanofi Aventis
IV II-III
AG014699 (PARP-1/2 IC50 1,4 nM)
Pfizer IV (oral) I-II
E7016(PARP-1/2 IC50 50 nM)
Eisai Oral (BBB) I
CEP-9722(PARP-1 IC50 20 nMPARP-2 IC50 6 nM)
Cephalon oral I-II
INO-1001(PARP-1/2 1 nM)
Pfizer IV I
MK-4827(PARP-1/2 IC50 3,8 nM)
Merck oral I
2003-5 First clinical trials with AG14699 and INO-1001
Graziani et al., Pharm. Res. 2005
Discovery of the activity in BRCA-defective tumors
One of the most exciting classes of compounds in oncology—inhibitors of the DNA repair enzyme poly-(ADP ribose) polymerase (PARP)—suffered a double blow, with Sanofi-aventis and AstraZeneca announcing disappointing results for their respective drugs.
Olaparib (Astra-Zeneca): clinical development in MONOTHERAPY
Phase 1 Phase II Phase III
Suspended phase III in breast cancer: focus on ovarian
Advanced Breast Cancer BRCA mutations (ICEBERG1)
Advanced Ovarian Cancer BRCA mutations (ICEBERG2)
Platinum resistant ovarian cancer (ICEBERG 3) vs Lip Dox
BRCA mutated or Recurrent High Grade Ovarian or Known BRCA mutated or Triple Negative Breast Cancer
Advanced solid tumours with BRCA mutations
Disseminated colorectal cancer
Advanced Solid tumors
First PARP inhibitor showing activity in BRCA-related ovarian and breast cancers
OLAPARIB: Phase II in BRCA1 OR BRCA2 MUTATED ADVANCED BREAST CANCER (ICEBERG 1)
Tutt A et al., The Lancet 376, 235, 2010
54 recurrent or advanced cancer patients with a median of 3 previous chemotherapy regimens
Low grade toxicity: 41% fatigue (grade 1 and 2) and nausea (grade 1 and 2)
41% objective response and tolerability of olaparib at 400 mg twice daily compares favorably with expected levels of activity (20–30% or less; 22% 100 mg) and toxicity of most chemotherapy agents used in patients previously treated with anthracycline and taxanes. Mean PFS 6 mo (3.8 mo 100 mg).
Recurrent BRCA Triple neg. 3m before and 2m after olaparib
CT scan of a BRCA Triple neg: arrows point to lung metastases before and after 180 d from olaparib
PET-CT scan of a BRCA Triple neg: arows point to hylar lympnodes and pleural disease before Olaparib
Tutt A et al., The lancet 376, 235, 2010
Before Olaparib After Olaparib
OLAPARIB: Phase II in BRCA1 OR BRCA2 MUTATIONS ADVANCED OVARIAN CANCER (ICEBERG 2)
• 90% sporadic and 10% have a predisposing genetic defect
• 90% of patients with familial predisposition carry the BRCA defect.
• Although women with BRCA-associated ovarian cancer might have higher response rates to chemotherapy and improved survival rates than do those with sporadic ovarian cancer, most with stages III and IV will ultimately relapse and die despite available therapies.
• Up until now, knowledge of a BRCA mutation has not affected the selection of treatment for ovarian cancer.
• Phase II: in 57 patients with 2 doses with a median of 3 previous chemotherapy regimens
• Phase II: in 57 patients with 2 doses with a median of 3 previous chemotherapy regimens
• 400 mg more effective than 100 mg: the efficacy comparison has to be cautious because patients allocation was not randomized (overall response rate 33% versus 13%). Mean PFS 5.8 mo (1.8 mo 100 mg).
• Mild to moderate adverse effects Audeh MW et al., The Lancet 376, 245, 2010
OLAPARIB: Phase II in BRCA1 or BRCA2 MUTATIONS ADVANCED OVARIAN CANCER
PLATINUM RESISTANT (ICEBERG 3)
• The PFS were 6.5 vs 8.8 vs 7.1 months for 200 mg, 400 mg, and liposomal doxorubicin arm, respectively.
• Olaparib did not reach the primary objective of improving PFS partly because of a better PFS seen in the liposomal doxorubicin arm than expected.
• Twice as many grade 3 toxicities were seen in the liposomal doxorubicin arm.
• Although reported as a negative study, this trial still shows consistent response and decreased toxicity with the use of single-agent olaparib in BRCA mutation ovarian cancer patients.
KAYE S et al., Ann Oncol 21:viii176, 537P (suppl 2), 245, 2010
Olaparib (Astra-Zeneca): clinical development in combination therapy
Phase 1 Phase II Phase IIIAdvanced ovarian cancer (+carboplatin and paclitaxel)
Recurrent Ovarian or Triple-Negative Breast Cancer(+cediranib) I-II
BRCA1/BRCA2-associated, hereditary, or triple negative metastatic or unresectable breast cancer or ovarian epithelial cancer.
(+carboplatin)
Triple Negative Breast Cancer and advanced ovarian cancer (+carboplatin
and or paclitaxel )
Metastatic melanoma (+dacarbazine)
Pancreatic cancer (+gemcitabine)
Recurrent or metastatic gastric cancer (+paclitaxel)
Breast, ovarian cervix, uterine unresponsive; men with BRCA metastatic
breast (+carboplatin)
Advanced solid tumours (+ topotecan or bevacizumb or cisplatin)
Advanced colorectal cancer (+irinotecan)
One of the concerns regarding the addition of PARP inhibitors to chemotherapy is the potential of enhancing toxicity
INIPARIB: A NON-COMPETITIVE PARP INHIBITOR
• Iniparib is an irreversible inhibitor• It ejects the Zn from the first zinc finger of
PARP-1 inactivating the enzyme and degrades PARP-1 activating a protease
• The first PARP inhibitor that has shown survival advantage in TNBC phase II
Iniparib (Sanofi-Aventis): clinical developmentPhase 1 Phase II Phase III
Triple Negative metastatic breast cancer (+gemcitabine-carboplatin)
Non Small Cell Lung Cancer (+gemcitabine-carboplatin)
Triple Negative breast cancer neoadjuvant (+gemcitabine-carboplatin or paclitaxel)
Platinum-Sensitive or -Resistant Recurrent Ovarian CancerNon Small Cell Lung Cancer (+gemcitabine-carboplatin) or monotherapy in BRCA
Triple negative Brain metastases (+ irinotecan)
Glioblastoma (+temozolomide)
Advanced or recurrent uterine carcinosarcma (+paclitaxel and carboplatin)
Advanced Solid tumors (+chemotherapy)
• About 15% of breast cancer; good response in the neo-adjuvant setting to taxanes and antracyclines.
• When metastatic disease develops the median survival is of approximately 1 year. No standard-of-care therapy exists for patients with metastatic triple-negative breast cancer. Current phase III comparing carboplatin versus docetaxel
• It shares clinical and pathological features with hereditary BRCA1-related breast cancers
• In sporadic triple-negative there is a dysregulation of BRCA1 or other components of HR
• Gemcitabine + carboplatin give 26-34% response rates
Phase II: INIPARIB PLUS CHEMOTHERAPY IN METASTATIC TRIPLE NEGATIVE BREAST CANCER
• 123 patients (>50% previously received taxanes and antracycline-based therapy and 10% bevacizumab) randomized to receive:– Iniparib (5,6 mg/kg d1,4,8,11) + gemcitabine and
carboplatin every 21 d– Gemcitabine (1000 mg/m2) and carboplatin
No differences in myelotoxicity between the two treatment arms
G+C+Iniparib G+C P
Response rate 52% 32% 0.02
Overall Survival (mo)
12,3(9,8-21,5) 7,7(6.5-13.3) 0,01
Adapted from O’Shaughnessy JO et al., The New England Journal of medicine 364: 205, 2011
INIPARIB AND PHASE III IN TNBC
• Sanofi-Aventis and its subsidiary, BiPar Sciences, at the end of January 2011 announced that a randomized Phase III trial evaluating Iniparib in 519 patients with metastatic disease did not meet the pre-specified criteria for significance for co-primary endpoints of overall survival and progression-free survival.
• The overall safety analysis indicates that the addition of iniparib did not significantly add to the toxicity profile of gemcitabine and carboplatin.
AG014699 (Pfizer): clinical development
Phase 1 Phase II Phase III
Ovarian breast cancer BRCA associated Monotherapy
BRCA 1 or BRCA 2 Mutation With Locally Advanced or Metastatic Breast or Advanced Ovarian Cancer (+cisplatin)Metastatic Melanoma (+temozolomide)
Adv. Solid tumours (+carboplatin
+ carboplatin and paclitaxel+cisplatin and pemetrexed
+epirubicin and cyclophosphamide)
Increased myelosuppression that required temozolomide dose reduction (in 32% of patients)
(chemotherapy-naïve)
VeIiparib (Abbott): clinical development (32 clinical studies)
Phase 1 Phase II Phase IIIHeavily treated metastatic colorectal cancer (+temozolomide)
Metastatic Breast Cancer (+temozolomide)
Hepatocellular carcinoma (+temozolomide)
Relapsed or Refractory Ovarian Cancer or Primary Peritoneal Cancer (+topotecan)
Metastatic prostate cancer (+temozolomide)
Pediatric recurrent refractory CNS Tumors (+temozolomide)
Advanced solid tumors and/or lymphoma (+folfiri or temozolomide or gemcitabine and carboplatin, cyclophosphamide, topotecan)
Acute Leukemia (+temozolomide)
Newly Diagnosed Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer
(+carboplain, paclitaxel and bevacizumab)
Refractory BRCA-Positive Ovarian, Primary Peritoneal or Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, Triple-Negative
Breast Cancer, and Low-Grade Non-Hodgkin's Lymphoma (+cyclophosphamide)
Recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer or metastatic breast cancer (+liposomal doxorubicin)
Primary and metastatic brain tumours (+whole brain irradiation)
Monotherapy: Leukemia/lymphoma/solid tumors, Recurrent and/or Metastatic Breast Cancer
VELIPARIB AND PHASE 0 TRIALS
• The first Phase 0 study under FDA new Exploratory Investigational New Drug was performed (a first-in-human clinical trial conducted under an exploratory IND that has no therapeutic or diagnostic intent and involves very limited human
exposure).
• Veliparib was chosen because it has a wide therapeutic index and a validated PD assay.
• The primary study end-point was target modulation by the PARP inhibitor measuring POLY(ADP-RIBOSE) levels in perypheral blood mononuclear cells (PBMC) and tumour biopsies.
PHASE 0 CLINICAL TRIAL AND VELAPARIB Poly(ADP) RIBOSE IN :
PBMC AND TUMOR BIOPSIES
Kummar et al., J Clin Oncol. 2009 ;27:2705-11.
RESISTANCE TO PARP INHIBITORS
• Secondary mutations of BRCA genes altering the reading frame to wild-type
1)Selection of pre-existing resistance clones2)Mutations acquired during treatment in cells genetically unstable
due to the lack of HR
SENSITIVITY OF OVARIAN CANCER TO PLATINUM AGENTS AND USE OF PARP INHIBITORS
• Platinum resistance:
disease progression within 6 months of prior platinum therapy
• Platinum refractory disease: disease progression on platinum therapy
• Fong PC et al., Journal of Clnical Oncology 28, 2512, 2010: Olaparib induced objective response 46.2% in platinum sensitive patients (6/13), 33.5% in platinum-resistant patients (8/24), 0% in platinum-refractory patients(0/13)
•Resistance to platinum is associated with decreased sensitivity to PARP inhibitors since platinum sensitivity may be in part related to BRCAness.
•Platinum-resistant tumors without secondary BRCA2 mutations may remain sensitive to PARP inhibitors
RESISTANCE TO PARP INHIBITORS
• Up-regulation of p-glycoprotein (Pgp) efflux pump
CHALLENGING TASKS
• (1) To determine the optimal chemotherapy backbone to combine with PARP inhibitors
• (2) To balance the benefit and toxicity risk when PARP inhibitors are used in combination therapies
• (3) To define the most effective schedule of administration (i.e., continuous versus intermittent dosing with chemotherapy: higher myelotoxicity; concomitant or sequence treatment)
CHALLENGING TASKS
• (4) To define more precisely the patient population most likely to respond: potential signature of BRCAness (e.g. 60-gene assay to identify BRCAness profile)
• (5) Potential prophylactic use for BRCA1 and BRCA2 mutation carriers: potential long-term toxicity
• (6) PARP-1 expression/activity levels???? (HR-deficient cancers have higher PARP-1 levels)
• (7) To discover and validate candidate biomarkers to predict responders [i.e., γH2AX, RAD51 (as a marker of intact HR), germline DNA studies,etc.]
BRCA SIGNATURE
Konstantinopoulos e al., JCO 2010, 28:355
H2AX and RAD51 and HR function
• A key component in DNA repair is the histone protein H2AX, which becomes rapidly phosphorylated to form large numbers of γH2AX at nascent DSB, creating a focus where proteins involved in DNA repair and chromatin remodeling accumulate (pink spots).
• Rad51 is a crucial downstream protein involved in HR repair, which is relocalized within the nucleus in response to DNA damage to form distinct foci that are thought to represent assemblies of proteins at these sites of HR repair (green spots).
PRESENCE OF H2AX AND DECREASE OF RAD51 INDICATE REDUCED HR FUNCTION AND SENSITIVITY TO PARP INHIBITORS
CHALLENGING TASKS:HOW TO OVERCOME RESISTANCE TO PARP
INHIBITORS
• 6-THYOGUANINE: it is not substrate of Pgp and reactivation of HR is not sufficient to repair lesions induced by 6-Thyoguanine
• Inhibitors of Pgp
• Proteasome inhibitors: down-regulation of Pgp
WHAT IS GOINGO TO BE THE FUTURE OF PARP INHIBITORS?
• Trials directed at subsets of patients who are most likely to respond to PARP inhibitors
• Trials in combination with chemotherapeutic agents for which preclinical studies have indeed shown synergy with PARP inhibitors
Indicare quale tra queste affermazioni riguardante gli inibitori di PARP è SBAGLIATA:
1.Olaparib ha mostrato attività antitumorale in monoterapia nei tumori con mutazioni di BRCA1 o BRCA2
2.Potenziano l’attività antitumorale della temozolomide inibendo il sistema di riparo per escissione delle basi
3.Potenziano l’attività antitumorale dei derivati delle camptotecine, che inibiscono la Topoisomerasi 1, rendendo più lento il processo di riparo del DNA
4.La maggior parte degli inibitori di PARP compete con il NAD per il legame al sito catalitico dell’enzima
5.Potenziano l’attività antitumorale di trastuzumab (anticorpo monoclonale anti-HER2) nei tumori della mammella triple negative
20%
20%
20%
20%
20%
Standard
010
Indicare quale tra queste affermazioni riguardante gli inibitori di PARP è SBAGLIATA:
1.L’Iniparib è un inibitore di PARP irreversibile, non competitivo
2.La mancata formazione di foci di RAD51 nel tumore in seguito a trattamento con inibitore di PARP potrebbe rappresentare un fattore predittivo di risposta al farmaco
3.I tumori ovarici associati a mutazioni di BRCA1 o BRCA2 e sensibili ai composti del platino sono in genere più sensibili agli inibitori di PARP rispetto ai tumori refrattari al platino (cioè che vanno in progressione durante la terapia con composti del platino)
4.Olaparib, un inibitore di PARP che supera la barriera emato-encefalica, in studi di fase II è stato associato a carboplatino e gemcitabina per il trattamento del glioblastoma multiforme
5.La resistenza agli inibitori di PARP può essere dovuta a nuove mutazioni di BRCA1 o BRCA2, che ripristinano l’espressione della normale proteina corrispondente, o ad elevata espressione di pompe di efflusso della famiglia della Multi Drug Resistance
20%
20%
20%
20%
20%
Standard
010
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