Maurizio D Incalci, MD Department of Oncology Mario Negri Institute, Milan, Italy

Transcription

1 Maurizio D Incalci, MD Department of Oncology Mario Negri Institute, Milan, Italy Oncologic Therapy Personalization: from basic research to clinical application Limits of: BASIC RESEARCH Reggio Emilia, April 16, 2010

2 DRUG DOSE PLASMA LEVELS PK NEOPLASTIC AND NORMAL TISSUE LEVELS PD PHARMACOLOGICAL EFFECTS (ANTITUMOR ACTIVITY TOXICITY)

3 DRUG ABSORPTION BLOOD LEVELS TISSUE DISTRIBUTION METABOLISM EXCRETION

4 ANTICANCER DRUG CONCENTRATIONS IN TUMOR

5 ANTICANCER DRUG CONCENTRATIONS IN TUMOR HOST FACTORS

6 HOST FACTORS INFLUENCING DRUG CONCENTRATIONS IN TUMORS GENERAL - AGE - GENDER - RACE - BODY WEIGHT - CO MORBIDITY

7 HOST FACTORS INFLUENCING DRUG CONCENTRATIONS IN TUMORS INTESTINAL ABSORPTION - NAUSEA, VOMITING - GASTRIC ACID SECRETION - DISSOLUTION OF TABLETS - INTERACTIONS WITH HERBAL REMEDIES, FOODS AND DRUGS - GENETIC DIFFERENCES IN CYTOCHROME P450, DRUG EFFLUX AND TRANSPORTERS UPTAKE

8 GRAPEFRUIT JUICE INHIBITS INTESTINAL ACTIVITY CYP3A4 CONSEQUENT INCREASE OF DRUG ABSORPTION

9 VARIABILITY OF PLASMA LEVELS IN PATIENTS AFTER ORAL mg/m 2 OF 4 DEMETHOXY DAUNORUBICIN PATIENT NUMBER AUC ng/ml x h ZANETTE et al., 1990

10 HOST FACTORS INFLUENCING DRUG CONCENTRATIONS IN TUMORS TISSUE DISTRIBUTION - BLOOD BRAIN BARRIER - PRESENCE OF ASCITES AND PLEURAL EFFUSION - AMOUNT OF BODY FAT - PLASMA ALBUMINS AND α ACID GLYCOPROTEINS - INTERACTIONS WITH HERBAL REMEDIES, FOODS AND DRUGS - GENETIC DIFFERENCES IN CYTOCHROME P450, DRUG EFFLUX AND TRANSPORTERS UPTAKE

11 DISTRIBUTION OF ALTRETAMINE (MICE) TISSUE AUC TISSUE/PLASMA TUMOR (M5076) 6 LIVER 16 SPLEEN 25 KIDNEY 17 HEART 10 BRAIN 4 ADIPOSE TISSUE 417 LYMPHONODES 226 SMALL INTESTINE 38 D INCALCI, 1987

12 HOST FACTORS INFLUENCING DRUG CONCENTRATIONS IN TUMORS METABOLISM - LIVER DISFUNCTIONS - ALTERED HEPATIC BLOOD FLOW - REDUCED LIVER MASS - INFLAMMATION - INTERACTIONS WITH HERBAL REMEDIES, FOODS AND GRUGS - GENETIC DIFFERENCES IN CYTOCHROME P450, DRUG EFFLUX AND TRANSPORTERS UPTAKE

13 SUPERFAMILY OF CYTOCHROME P450 CYP 2D6 GENETIC POLYMORPHISM (78 VARIANTS) DETERMINES POOR, INTERMEDIATE, EXTENSIVE, ULTRARAPID METABOLIZERS

14 Stearns et al., 2003

15 J.W. Watters and H.L. McLeod Biochimica et Biophysica Acta 1603 (2003)

16 J.W. Watters and H.L. McLeod Biochimica et Biophysica Acta 1603 (2003)

17 HOST FACTORS INFLUENCING DRUG CONCENTRATIONS IN TUMORS EXCRETION - ALTERED BILIARY FLOW - RENAL INSUFFICIENCY - URINARY ph - INTERACTIONS WITH HERBAL REMEDIES, FOODS AND GRUGS - GENETIC DIFFERENCES IN CYTOCHROME P450, DRUG EFFLUX AND TRANSPORTERS UPTAKE

18 ANTICANCER DRUG CONCENTRATIONS IN TUMOR HOST FACTORS TUMOR FACTORS

19 TUMOR FACTORS INFLUENCING DRUG CONCENTRATIONS IN TUMORS INTRATUMORAL BLOOD CONCENTRATION BLOOD FLOW, NUMBER OF VESSELS, ARCHITECTURE, PERMEABILITY, FENESTRATION, INTRAVASCULAR THROMBI, DEFECTIVE LYMPHATIC DRAINAGE

20 PATIENT TUMOR METASTASES SUBCUTANEOUS OMENTUM * * * * ALTRETAMINE µg/g Damia, D Incalci, 1995

21 TUMOR FACTORS INFLUENCING DRUG CONCENTRATIONS IN TUMORS INTRATUMORAL BLOOD CONCENTRATION BLOOD FLOW, NUMBER OF VESSELS, ARCHITECTURE, PERMEABILITY, FENESTRATION, INTRAVASCULAR THROMBI, DEFECTIVE LYMPHATIC DRAINAGE TUMOR CELL DENSITY TRIDIMENTIONAL SIZE, NECROTIC TISSUE, EXTRACELLULAR MATRIX, CONTENT OF COLLAGEN, INTERSTITIAL PRESSURE, HETEROGENEITY OF DRUG DISTRIBUTION

22 Au et al., 2001

23 DRUG DOSE PLASMA LEVELS PK NEOPLASTIC AND NORMAL TISSUE LEVELS PD PHARMACOLOGICAL EFFECTS (ANTITUMOR ACTIVITY TOXICITY)

24 MOST IMPORTANT PD APPLICATIONS ACTIVATING MUTATIONS OF THE KINASE ENCODING GENES (e.g. EGFR, HER2, KRAS AND KIT) IN PREDICTING RESPONSE TO KINASE INHIBITORS. GERMLINE MUTATIONS OF BRCA1 AND 2 GENES IN PREDICTING RESPONSE TO POLY(ADENOSINE DIPHOSPHATE RIBOSE) POLYMERASE INHIBITORS. MICROARRAY BASED GENE SIGNATURES OF PROGNOSIS IN BREAST CANCER FOR PREDICTING BENEFITS FROM ADJUVANT CHEMOTHERAPY GENETIC VARIANTS OF DRUG METABOLIZING AND DNA REPAIR ENZYMES FOR THE PREDICTION OF DRUG TOXICITY. PROMOTER METHYLATION OF DNA REPAIR GENE IN PREDICTING RESPONSE TO METHYLATING AGENTS.

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30 Correlation between mutated KIT exons and response to Imatinib Exon 11 Exon 9 Exon 13 Exon 17 WT Imatinib response

31 Prediction of response:sunitinib p PR c-kit none PDGFRα exon 9 exon 11 exon 18 Demetri GD, ASCO 2004

32 Activity in STS vs MLS all MLS No. Pts OR 8% 50% 20% 88% Median PFS, mos 3 14 F Grosso et al, Lancet Oncology, 8: (2007)

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34 Myxoid liposarcomas are responsive to Trabectedin Patterns of tumor response included dimensional RECIST OR in ~45%, and tumor tissue changes in 65%; this tissue response preceded dimensional regression in 62% of RECIST responders ( delayed responses ) Median PFS was 17 mos, and treatment was maintained for long in many patients A selective mechanism of action for Trabectedin in this translocation related sarcoma is actively sought

35 FUS-Chop variants and patients response to trabectedin Type 1 Type 1 del Type 1 del Type 2 Type 3 Type 4 Type 6 del Type 1 del Type 1, 1 del, 4 Type 2 Type 3 Type 6 del

36 CONCLUSIONS FOR MOST ANTICANCER TREATMENTS IT IS STILL UNFEASEABLE TO PERSONALIZE THE THERAPY BECAUSE OF THE COMPLEXITY AND MULTIPLICITY OF PK PD FACTORS. IN SOME CASES RESISTANCE CAN BE PREDICTED BASED ON PK PD EVALUATION ( e.g. METHYLATING AGENTS) IIN SOME CASES TOXICITY CAN BE PREDICTED BASED ON PK PD EVALUATION (e.g. PDP DEFICIENCY). FOR SPECIFIC DISEASES AND CLASSES OF DRUGS (e.g. KINASES INHIBITORS) THE CHARACTERIZATION OF THE TARGET AND RELATED PATHWAYS CAN BE A USEFUL MEAN TO PREDICT RESISTANCE AND INDICATE POSSIBLE ALTERNATIVE COMPOUNDS TO BE USED.