Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(6), P. 323 - 339

Published: March 9, 2022

Language: Английский

---

Combining DNA damaging therapeutics with immunotherapy: more haste, less speed

British Journal of Cancer, Journal Year: 2017, Volume and Issue: 118(3), P. 312 - 324

Published: Nov. 9, 2017

The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents actually promote immunogenic cell death, alter inflammatory milieu tumour microenvironment and/or stimulate neoantigen production, thereby activating an response. Some notable combinations have moved forward into clinic, showing promise phase I–III trials, whereas others proven toxic, and challenging deliver. In this review, we discuss emerging data how enhance properties malignant focussing especially expansion repertoires. We best strategically combine therapeutics immunotherapy, challenges successfully delivering these regimens patients. With overwhelming number chemotherapy/immunotherapy trials process, clear hypothesis-driven are refine choice combinations, determine timing sequencing order immunological memory improve maintained durable response rates, minimal toxicity.

Language: Английский

---

First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors

Cancer Discovery, Journal Year: 2020, Volume and Issue: 11(1), P. 80 - 91

Published: Sept. 29, 2020

Abstract Targeting the ataxia telangiectasia and RAD3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects replication stress, including inactivation of mutated (ATM) signaling. We report dose-escalation portion phase I first-in-human trial oral ATR inhibitor BAY 1895344 intermittently dosed 5 to 80 mg twice daily in 21 patients advanced solid tumors. The MTD was 40 3 days on/4 off. Most common adverse events were manageable reversible hematologic toxicities. Partial responses achieved 4 stable disease 8 patients. Median duration 315.5 days. Responders had ATM protein loss and/or deleterious mutations received doses ≥40 daily. Overall, is well tolerated, antitumor activity against cancers certain DDR defects, loss. An expansion continues deficiency. Significance: Oral tolerable, heavily pretreated various tumors, particularly those protein; pharmacodynamic results supported mechanism action increased damage. Further study warranted this patient population. See related commentary by Italiano, p. 14. This article highlighted In Issue feature, 1

Language: Английский

---

Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

Cells, Journal Year: 2021, Volume and Issue: 10(3), P. 659 - 659

Published: March 16, 2021

Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine cancer. Small molecule inhibitors monoclonal antibodies directed at relevant cancer-related proteins have been instrumental delivering successful of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) solid tumors tamoxifen ER positive breast trastuzumab HER2-positive cancer). However, inherent limitations such as drug toxicity, well acquisition de novo or acquired mechanisms resistance, still cause treatment failure. Here we provide an up-to-date review the successes current targeted therapies highlight how recent technological advances provided a level understanding molecular complexity underpinning resistance therapies. We also raise three basic questions concerning discovery based on markers selected pathways, further discuss combination may become preferable approach over monotherapy treatments. Finally, consider novel therapeutic developments that complement delivery significantly improve clinical response outcomes patients.

Language: Английский

---

Functional interrogation of DNA damage response variants with base editing screens

Cell, Journal Year: 2021, Volume and Issue: 184(4), P. 1081 - 1097.e19

Published: Feb. 1, 2021

Language: Английский

---