Mechanisms of Action and Preclinical Activity: agents used in mCT

(1)

Mechanisms of action &

pre-clinical activity

Agents used in Metronomics

Mechanisms of action &

pre-clinical activity

Agents used in Metronomics

Marie Sklodowska- Curie Fellowship

Eddy Pasquier, PhD

Marie Curie Fellow – Aix‐Marseille University (France) Honorary Fellow – Children’s Cancer Institute (Australia)

Co‐founder – Metronomics Global Health Initiative

Eddy Pasquier, PhD

Marie Curie Fellow – Aix‐Marseille University (France) Honorary Fellow – Children’s Cancer Institute (Australia)

Co‐founder – Metronomics Global Health Initiative

(2)

Clinical Cancer Research 1996

Blood 1999

Journal of Hematotherapy & Stem Cell Research 2003

(3)

Anti-angiogenic activity of paclitaxel Anti-angiogenic activity of paclitaxel

[Paclitaxel] (nM) [Paclitaxel] (nM)

% of control% of control

Cytostatic effect Cytotoxic effect

(4)

Microtubule dynamic instability Microtubule dynamic instability

Time-lapse videomicroscopy following micro-injection of rhodamine-tubulin in endothelial cells

(5)

Interphasic functions of microtubules

Inhibition of cell motility and differentiation

Anti-angiogenic activity Anti-angiogenic activity

ow concentrations

INCREASE INCREASE

Cytotoxic concentrations

SUPPRESSION SUPPRESSION

Microtubule dynamics Microtubule dynamics

slight strong

Mitotic functions of microtubules

Inhibition of cell proliferation

Apoptosis induction Apoptosis

induction Mitotic

arrest Mitotic

arrest

Inhibition of proliferation and cytotoxicity are not required for the anti-angiogenic activity of MTAs Inhibition of proliferation and cytotoxicity are not

required for the anti-angiogenic activity of MTAs

Pasquier et al., Cancer Res 2005 Pourroy et al., Cancer Res 2006

(6)

Nature Reviews Cancer, 2004

(7)

(8)

(9)

Cancer Research, 2003

(10)

(11)

PNAS, 2003

(12)

(13)

Adapted from Pasquier et al., Nat Rev Clin Oncol 2010

(14)

Galluzzi et al., Nature Reviews Drug Discovery, 2012

(15)

(16)

Cancer Research 2007

Metronomic chemotherapy decreases cancer cell stemness

(17)

International Journal of Cancer 2013

(18)

PNAS 2009

Cancer Research 2002

2011

(19)

(20)

Vinblastine

Microtubule-targeting agent

Etoposide

Topoisomerase II inhibitor

Mafosfamide

Alkylating agent

Long-term effects of chemotherapy on vascular endothelial cells

MAXIMUM-TOLERATED DOSE (MTD) versus LOW-DOSE METRONOMIC (LDM) MAXIMUM-TOLERATED DOSE (MTD) versus LOW-DOSE METRONOMIC (LDM)

METRONOMICS Global Health Initiative

(21)

LOW-DOSE METRONOMIC (LDM) Treatment 5 days/week with IC₁ LOW-DOSE METRONOMIC (LDM)

Treatment 5 days/week with IC₁ MAXIMUM-TOLERATED DOSE (MTD)

Treatment every 2 weeks with IC₈₀

MAXIMUM-TOLERATED DOSE (MTD) Treatment every 2 weeks with IC₈₀

(22)

Metronomic mafosphamide induces senescence in vascular endothelial cells

-galactosidase staining, 3 weeks incubation with MFA

BMH29L BMH29L

(23)

LOW-DOSE METRONOMIC (LDM) Treatment 5 days/week with IC₁ LOW-DOSE METRONOMIC (LDM)

Treatment 5 days/week with IC₁ MAXIMUM-TOLERATED DOSE (MTD)

Treatment every 2 weeks with IC₈₀

MAXIMUM-TOLERATED DOSE (MTD) Treatment every 2 weeks with IC₈₀

(24)

LDMMTD

Control Vinblastine Etoposide

-20%

N.S

-33%

-39%

Matrigel^TM assay – 8h incubation Matrigel^TM assay – 8h incubation

LDM and MTD chemotherapy differentially impact on the angiogenic potential of endothelial cells LDM and MTD chemotherapy differentially impact

on the angiogenic potential of endothelial cells

(25)

*

**

***

*

**

*

Vinblastine Etoposide Paclitaxel

Growth inhibition assay – 72h drug incubation Growth inhibition assay – 72h drug incubation

LDM and MTD chemotherapy differentially impact on the chemosensitivity of endothelial cells

*** ***

***

**

*

* *

*

* Vinblastine

(5 nM)

Etoposide (10 μM)

Paclitaxel (10 nM)

Matrigel^TM assay – 8h drug incubation Matrigel^TM assay – 8h drug incubation

Pasquier et al., Angiogenesis 2013

(26)

Adapted from André et al., Nat Rev Clin Oncol 2014 Doxorubicin

Doxorubicin

Vincristine Vincristine

Cyclophosphamid e Temozolomide Cyclophosphamid e Temozolomide Methotrexate Methotrexate

Gemcitabine Gemcitabine

MTAs MTAs

Cyclophosphamid e

Cyclophosphamid eGemcitabine

Gemcitabine Etoposide Etoposide

Cyclophosphamid e

Doxorubicin Doxorubicin Topotecan Topotecan Gemcitabine Gemcitabine

(27)

DRUG REPOSITIONING

(28)

Adapted from André et al., Lancet Oncol 2013

(29)

Nature Reviews Clinical Oncology 2015

(30)

June 2008, 358 (24): 2649-51

9 weeks of age

After 4 weeks of corticosteroids

10 weeks of age

After 1 week of propranolol

9 months of age

After 7 months of propranolol

(31)

June 2008, 358 (24): 2649-51

Could β-blockers be

used in cancer treatment

?

Could β-blockers be

used in cancer treatment HYPOTHESIS?

β-blockers may be able to increase the efficacy of chemotherapy through direct effects on cancer

cells or via anti-angiogenic mechanisms

(32)

Potentiation of the anti-angiogenic effects of chemotherapy by

propranolol

Potentiation of the anti-angiogenic effects of chemotherapy by

propranolol

Matrigel^TM assay – 8h drug incubation Matrigel^TM assay – 8h drug incubation

No propranolol10 µM propranolol

10 nM paclitaxel 50 nM paclitaxel

-44%

N.S

-71%

-76% -92%

No paclitaxel

(33)

Oncotarget, 2011 British J Cancer, 2013

Vehicle – Day 4

VCR – Day 4

VCR – Day 7

**

***

* *

**

*

Vincristine alone + Propranolol + Carvedilol + Nebivolol

(34)

Spheroid volume (mm3 )

Time (h)

*** ** ***

*

***

Tumour spheroid model

Control

Propranolol

Vinblastine

Combination

-59%

-19%

-20%

EBioMedicine, in press

(35)

EBioMedicine, in press

Diagnosis 3 months 12 months

Diagnosis 8 months

New treatment protocol: propranolol (40 mg; BID) in combination with metronomic vinblastine (6 mg/m²; weekly) and methotrexate (35 mg/m²; weekly)

100 % response based on RECIST criteria

11+ months median PFS 16+ months median OS

100 % response based on RECIST criteria

11+ months median PFS 16+ months median OS

2 clinical trials starting in 2016, using propranolol in combination with metronomic chemotherapy

(36)

(37)

The very concept of “repeated administration of low‐dose chemotherapy over a long period of time” covers numerous possibilities:

• What is a small dose?

•What is a repeated administration?

• What is a long period of time?

Computational oncology &

metronomics

(38)

metronomics

Examples of oral vinorelbine protocols used in the clinic

(39)

Different PK profile

Similar toxicity profile

Higher efficacy

Briasoulis et al. Model-driven

PK

Tox

Eff

Mathematical modeling suggests that a D1-D2-D4 protocol at 60-30-60mg would be more efficient than the D1-D3-D5 protocol at 50-50-50mg recommended by Briasoulis et al. (BMC Cancer 2013)

metronomics

(40)

TAKE HOME MESSAGES TAKE HOME MESSAGES

Metronomic chemotherapy is a form of multi-targeted therapy

Mathematical modeling can help optimize metronomic chemotherapy protocols

Every drug has its own unique properties and must be rationally selected

Drug repositioning provides a unique opportunity to further increase the efficacy of metronomic chemotherapy

(41)

ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS

Sydney Pr Maria Kavallaris Janine Street

Charlotte Pouchy Maria-Pia Tuset Snega Sinnappan Jayne Murray

Dr Karen MacKenzie

Marseille Pr Diane Braguer Dr Nicolas André Dr Manon Carré Dr Joseph Ciccolini Seimia Chebbi

Arnaud Mansour

Mumbai

Dr Shripad Banavali

METRONOMICS Global Health Initiative

(42)

Mathematical modeling can help identify an optimal solution among numerous combinations

Once built and validated, the model can generate an infinity of simulations until a solution to a given problem is found

This strategy is based upon the use of any data made available which are likely to help build a mathematical model and identify its parameters

+

metronomics

(43)

• Doses: 1, 2, 3.3, 5, 10, 30 mg/kg…

• Schedule: daily, 1-day on / 2-days off, 3-weeks on / 1-week off …

• Duration: 3 weeks, 4 weeks, continuous…

Metronomic gemcitabine Metronomic gemcitabine

(44)

PK modeling

Effects on:

cancer cells

endothelial cells Tumour growth (Gompertz)

Anti-angiogenic effect

Mathematical modeling Mathematical modeling

(45)

Can metronomic scheduling improve the efficacy of gemcitabine against resistant

neuroblastoma ?

GMZR

100 mg/kg i.p.

QW for 4 weeks

VS.

METROGEM

1 mg/kg or 0.5 mg/kg Continuous for 4 weeks

Standard Model-driven

MetroGEM study MetroGEM study

(46)

• Drug Monitoring (LC-MS/MS)

While MTDGem led to a Cmax of 80 µg/ml, 0.1 µg/ml steady state concentrations were observed with MetroGem

MTDGem MetroGem1 MetroGem1

GEM _dFdU

MTDGem

(47)

Vascular Density-1(AngioSense 780)

MetroGem led to reduced vascular density

Control 100 mg/kg MetroGem1 MetroGem0.5

(48)

MTD showed little efficacy, while MetroGem induced a significant reduction in tumour growth (p<0.05 ANOVA). Disease stabilization was maintained at least 40 days after stopping treatment.

0,00E+00 1,00E+02 2,00E+02 3,00E+02 4,00E+02 5,00E+02 6,00E+02 7,00E+02 8,00E+02

0 10 20 30 40 50 60 70 80 90 100

Tumor growth (106 p/sec)

MTDGem (100 mg/kg)

MetroGEM (0.5 mg/kg) MetroGEM (0.5 mg/kg)