Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors by-passed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment. © 2014 IBCB, SIBS, CAS All rights reserved

Microscopic structures and dynamics of high- and low-density liquid trans-1,2-dichloroethylene

We present a study of the dynamics and structural changes for trans-1,2-dichloroethylene between high-and low-density liquids using neutron-scattering techniques (diffraction, small-angle neutron scattering, and time of flight spectroscopy) and molecular-dynamics simulations. We show that changes in the short-range ordering of molecules goes along with a change in the molecular dynamics: both structure and dynamics of the high-density liquid are more cooperative than those of the low-density liquid. The microscopic mechanism underlying the cooperative motions in the high-density liquid has been found to be related to the backscattering of molecules due to a strong correlation of molecular ordering

MONALEESA-3 : A phase III study of Ribociclib (LEE011) with Fulvestrant for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in postmenopausal women who have received no or only one line of prior endocrine therapy

peer reviewe

Phase III study of Ribociclib (LEE011) in combination with Fulvestrant for the treatment of postmenopausal patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) who have received no or only one line of prior endocrine treatment : MONALEESA-3

peer reviewe

Phase III study of Ribociclib (LEE011) plus Fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer who have received no or only one line of prior endocrine treatment : MONALEESA-3

peer reviewe

Disorder effects on heat transport properties of orientationally disordered crystals

Postprint (published version