Integrin Signaling Shaping BTK-Inhibitor Resistance.

Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d/CD29 heterodimer, is a beta1 integrin implicated in therapy resistance in both solid tumors and haematological malignancies such as chronic lymphocytic leukemia (CLL). A complex inside-out signaling mechanism activates VLA-4, which might include several therapeutic targets for CLL. Treatment regimens for this disease have recently shifted towards novel agents targeting BCR signaling. Bruton's tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an ongoing interaction of CD49d-expressing leukemic cells with their surrounding tissue, which may reduce the success of therapy with BTK inhibitors and increases the need for alternative therapies. In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance.

Food constituent- and herb-drug interactions in oncology: Influence of quantitative modelling on Drug labelling.

AIMS: Herbal products, spices and/or fruits are perceived as inherently healthy; for instance, St. John's wort (SJW) is marketed as a natural antidepressant and patients often self-administer it concomitantly with oncology medications. However, food constituents/herbs can interfere with drug pharmacokinetics, with risk of altering pharmacodynamics and efficacy. The objective of this work was to develop a strategy to prioritize herb- or food constituent-drug interactions (FC-DIs) to better assess oncology drug clinical risk. METHODS: Physiologically based pharmacokinetic (PBPK) models were developed by integrating in vitro parameters with the clinical pharmacokinetics of food constituents in grapefruit juice (bergamottin), turmeric (curcumin) or SJW (hyperforin). Perpetrator files were linked to verified victim PBPK models through appropriate interaction mechanisms (cytochrome P450 3A, breast cancer resistance protein, P-glycoprotein) and applied in prospective PBPK simulations to inform the likelihood and magnitude of changes in exposure to osimertinib, olaparib or acalabrutinib. RESULTS: Reported FC-DIs with oncology drugs were well recovered, with absolute average fold error values of 1.10 (bergamottin), 1.05 (curcumin) and 1.01 (hyperforin). Prospective simulations with grapefruit juice and turmeric showed clinically minor to insignificant changes in exposure (<1.50-fold) to acalabrutinib, osimertinib and olaparib, but predicted 1.57-fold FC-DI risk between acalabrutinib and curcumin. Moderate DDI risk was expected when acalabrutinib, osimertinib or olaparib were dosed with SJW. CONCLUSIONS: A model-informed decision tree based on mechanistic understanding of transporter and/or enzyme-mediated FC-DI is proposed based on bergamottin, curcumin and hyperforin FC-DI clinical data. Adopting this quantitative modelling approach should streamline herbal product safety assessments, assist in FC-DI management, and ultimately promote safe clinical use of oncology drugs.

Acalabrutinib and its use in treatment of chronic lymphocytic leukemia.

Acalabrutinib received an accelerated US FDA approval for patients with relapsed/refractory mantle cell lymphoma in 2017 and is currently being evaluated in chronic lymphocytic leukemia (CLL). To date, ibrutinib is the only Bruton tyrosine kinase (BTK) inhibitor that's approved for treatment of CLL. Acalabrutinib is a second generation BTK inhibitor that binds covalently to the Cys481 residue on BTK and has half maximal inhibitory concentration (IC50) of 3 nM. In preclinical mouse models, acalabrutinib significantly reduced proliferation of CLL cells. Results of Phase I/II trials revealed overall response rates (ORR) of 96% in treatment-naive, 93% in relapsed/refractory and 76% in ibrutinib intolerant patients with CLL. The most common adverse effects (>20%) were grade 1-2 comprising constitutional symptoms, GI toxicity, rash and myelosuppression. There were limited grade 3 or 4 toxicities, involving syncope, pneumonia, hypertension, atrial fibrillation, neutropenia and thrombocytopenia.