Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review

Breast cancer is the global leading cause of cancer-related death in women and it represents a major health burden worldwide. One of the promising breast cancer therapeutic avenues is through small molecule inhibitors (SMIs) which have undergone rapid progress with successful clinical trials. Recently, three emerging and vital groups of proteins are targeted by SMIs for breast cancer treatment, namely cyclin-dependent kinase 4 and 6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP) and phosphoinositide 3-kinase (PI3K). Several of these inhibitors have been approved for the treatment of breast cancer patients or progressed into late-stage clinical trials. Thus, modeling from these successful clinical trials, as well as their limitations, is pivotal for future development and trials of other inhibitors or therapeutic regimens targeting breast cancer patients. In this review, we discuss eight recently approved or novel SMIs against CDK4/6 (palbociclib, ribociclib and abemaciclib), PARP (olaparib, veliparib and talazoparib), and PI3K (buparlisib and alpelisib). The mechanisms of action, series of clinical trials and limitations are described for each inhibitor.

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Trastuzumab Mechanism of Action; 20 Years of Research to Unravel a Dilemma

Cancers ◽

10.3390/cancers13143540 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3540

Author(s):

Hamid Maadi ◽

Mohammad Hasan Soheilifar ◽

Won-Shik Choi ◽

Abdolvahab Moshtaghian ◽

Zhixiang Wang

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Cancer Patients ◽

Mechanism Of Action ◽

Mechanisms Of Action ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Insight Into ◽

Positive Breast Cancer

Trastuzumab as a first HER2-targeted therapy for the treatment of HER2-positive breast cancer patients was introduced in 1998. Although trastuzumab has opened a new avenue to treat patients with HER2-positive breast cancer and other types of cancer, some patients are not responsive or become resistant to this treatment. So far, several mechanisms have been suggested for the mode of action of trastuzumab; however, the findings regarding these mechanisms are controversial. In this review, we aimed to provide a detailed insight into the various mechanisms of action of trastuzumab.

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Breast Cancer in the Elderly

Journal of Clinical Oncology ◽

10.1200/jco.2006.10.2079 ◽

2007 ◽

Vol 25 (14) ◽

pp. 1882-1890 ◽

Cited By ~ 117

Author(s):

Diana Crivellari ◽

Matti Aapro ◽

Robert Leonard ◽

Gunter von Minckwitz ◽

Etienne Brain ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Life Expectancy ◽

Cancer Patients ◽

Disease Free Survival ◽

Cost Benefit ◽

The Elderly ◽

Breast Cancer Patients ◽

Younger Women ◽

Based Medicine

Screening and adjuvant postoperative therapies have increased survival among women with breast cancer. These tools are seldom applied in elderly patients, although the usually reported incidence of breast cancer is close to 50% in women 65 years or older, reaching 47% after 70 years in the updated Surveillance, Epidemiology, and End Results (SEER) database. Elderly breast cancer patients, even if in good medical health, were frequently excluded from adjuvant clinical trials. Women age 70 years who are fit actually have a median life expectancy of 15.5 years, ie, half of them will live much longer and will remain exposed for enough time to the potentially preventable risks of a relapse and specific death. In the last few years, a new concern about this issue has developed. Treatment now faces two major end points, as in younger women: to improve disease-free survival in the early stages, and to palliate symptoms in advanced disease. However, in both settings, the absolute benefit of treatment is critical because protecting quality of life and all its related aspects (especially functional status and independence), is crucial in older persons who have more limited life expectancy. Furthermore, the new hormonal compounds (aromatase inhibitors) and chemotherapeutic drugs (capecitabine, liposomal doxorubicin), are potentially less toxic than and equally as effective as older more established therapies. These new treatments bring new challenges including higher cost, and defining their benefit in elderly breast cancer must include an analysis of the cost/benefit ratio. These issues emphasize the urgent need to develop and support clinical trials for this older population of breast cancer patients both in the adjuvant and metastatic settings, a move that will take us from a prejudiced, age-based medicine to an evidence-based medicine.

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Preclinical and Clinical Effects of Mistletoe against Breast Cancer

BioMed Research International ◽

10.1155/2014/785479 ◽

2014 ◽

Vol 2014 ◽

pp. 1-15 ◽

Cited By ~ 42

Author(s):

Mohsen Marvibaigi ◽

Eko Supriyanto ◽

Neda Amini ◽

Fadzilah Adibah Abdul Majid ◽

Saravana Kumar Jaganathan

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Antitumor Activity ◽

Cancer Patients ◽

Remission Rate ◽

Self Regulation ◽

Herbal Medicines ◽

Clinical Effects ◽

Breast Cancer Patients ◽

Mistletoe Extract

Breast cancer is among the most frequent types of cancer in women worldwide. Current conventional treatment options are accompanied by side effects. Mistletoe is amongst the important herbal medicines traditionally used as complementary remedies. An increasing number of studies have reported anticancer activity of mistletoe extracts on breast cancer cells and animal models. Some recent evidence suggests that cytotoxic activity of mistletoe may be mediated through different mechanisms. These findings provide a good base for clinical trials. Various studies on mistletoe therapy for breast cancer patients revealed similar findings concerning possible benefits on survival time, health-related quality of life (HRQoL), remission rate, and alleviating adverse reactions to conventional therapy. This review provides an overview of the recent findings on preclinical experiments and clinical trials of mistletoe for its cytotoxic and antitumor activity and its effect on HRQoL in breast cancer patients. Moreover, studies investigating molecular and cellular mechanisms underlying antitumor activity of mistletoe are discussed in this paper. The analyzed trials provided evidence that there might be a combination of pharmacological and motivational aspects mediated by the mistletoe extract application which may contribute to the clinical benefit and positive outcome such as improved HRQoL and self-regulation in breast cancer patients.

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