bims-cyhorp 2022-07-31 papers

Issue of 2022–07–31
five papers selected by
Piotr Okupski,

Int J Biol Macromol. 2022 Jul 22. pii: S0141-8130(22)01588-4. [Epub ahead of print]218 394-408

Structure-guided design and development of cyclin-dependent kinase 4/6 inhibitors: A review on therapeutic implications.

Mohd Yousuf, Manzar Alam, Anas Shamsi, Parvez Khan, Gulam Mustafa Hasan, Qazi M Rizwanul Haque, Md Imtaiyaz Hassan.

Cyclin-dependent kinase 6 (EC 2.7.11.22) play significant roles in numerous biological processes and triggers cell cycle events. CDK6 controlled the transcriptional regulation. A dysregulated function of CDK6 is linked with the development of progression of multiple tumor types. Thus, it is considered as an effective drug target for cancer therapy. Based on the direct roles of CDK4/6 in tumor development, numerous inhibitors developed as promising anti-cancer agents. CDK4/6 inhibitors regulate the G1 to S transition by preventing Rb phosphorylation and E2F liberation, showing potent anti-cancer activity in several tumors, including HR+/HER2- breast cancer. CDK4/6 inhibitors such as abemaciclib, palbociclib, and ribociclib, control cell cycle, provoke cell senescence, and induces tumor cell disturbance in pre-clinical studies. Here, we discuss the roles of CDK6 in cancer along with the present status of CDK4/6 inhibitors in cancer therapy. We further discussed, how structural features of CDK4/6 could be implicated in the design and development of potential anti-cancer agents. In addition, the therapeutic potential and limitations of available CDK4/6 inhibitors are described in detail. Recent pre-clinical and clinical information for CDK4/6 inhibitors are highlighted. In addition, combination of CDK4/6 inhibitors with other drugs for the therapeutic management of cancer are discussed.

Keywords: CDK4/6 inhibitors; Cancer therapy; Cyclin-dependent kinases; Drug design and development; Retinoblastoma; Structure-based drug design and discovery

DOI: https://doi.org/10.1016/j.ijbiomac.2022.07.156

Anticancer Res. 2022 Aug;42(8): 3913-3919

Everolimus for Treating Hormone Receptor-positive Metastatic Breast Cancer Previously Treated With Cyclin-dependent Kinase 4/6 Inhibitors.

Sae Kitano, Akiko Honda, Naoko Itoi, Tecchuu Lee.

BACKGROUND/AIM: Cyclin-dependent kinase (CDK) 4/6 inhibitors have become the standard of care as the first- and second-line treatments for hormone receptor-positive (HR+) or human epidermal growth factor receptor 2 (HER2)-negative metastatic and recurrent breast cancers. Although CDK 4/6 inhibitors can markedly prolong progression-free survival, there is no clear evidence of their post-treatment effects. The option of developing mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, has been discussed as a post-treatment option for such patients. This study aimed at determining everolimus' efficacy as a post-treatment option following CDK4/6 inhibitor administration in clinical settings.
PATIENTS AND METHODS: Thirteen patients who received everolimus as a post-treatment after CDK4/6 inhibitor therapy from December 2017 to July 2021 were retrospectively reviewed. The primary endpoint was progression-free survival; the secondary endpoints were overall response rate, clinical benefit rate, and overall survival.
RESULTS: The median patient age, progression-free survival, and overall survival were 59 years (range=44-76 years), 9.1 months (95% confidence interval=2.3 to not reached), and 37.4 months (95% confidence interval=12.3-37.4), respectively. The overall response rate and clinical benefit rate were 15.3% (2/13) and 46.2% (6/13), respectively.
CONCLUSION: Considering there is a mechanism of resistance to CDK4/6 inhibitors, everolimus would be important as an effective post-treatment for HR+ or HER2-negative metastatic and recurrent breast cancers treated with CDK4/6 inhibitors in clinical settings.

Keywords: CDK4/6 inhibitor; Everolimus; metastatic hormone receptor-positive breast cancer

DOI: https://doi.org/10.21873/anticanres.15885

J Oncol Pharm Pract. 2022 Jul 29. 10781552221117135

A multicentre study with real-world data of the use of palbociclib in the treatment of breast cancer: Treatment duration correlates with dose reductions.

Felice Musicco, Ruggero Lasala, Fiorenzo Santoleri, Alberto Costantini, Paolo Abrate, Maria Teresa Carretta, Enrica Maria Proli, Alessia Romagnoli, Nicola Petragnani, Francesco De Vita, Massimo Zeuli, Patrizia Vici, Massimo Sansone, Matilde Pasquantonio, Antonia La Malfa, Chiara Fulgenzio.

OBJECTIVE: Palbociclib, a highly selective reversible CDK4-6 kinase inhibitor, is indicated in combination with an aromatase inhibitor or in combination with fulvestrant in women who had received prior endocrine treatment. Studies have demonstrated the efficacy of palbociclib in combination with fulvestrant in increasing progression-free survival in patients who relapsed or progressed on previous endocrine therapy, or in combination with aromatase inhibitor in patients who had not received previous treatments. We analysed the prescribing patterns of palbociclib in real practice correlating it with the evidence of treatment-related toxicity management and to time-to-treatment discontinuation and treatment adherence.
METHODS: For the observational, retrospective study, data were collected from five Italian hospital centres that prescribed palbociclib between April 2017 and April 2020. Each centre provided data derived from an administrative database of adult patients treated with palbociclib for the two therapeutic indications.Treatment adherence was calculated using the proportion of days covered method while time-to-treatment discontinuation was defined as the difference between the first and last date treatment was administered plus the days ideally covered by the last date treatment was given.
RESULTS: There were 375 patients enrolled during the study period, of whom 159 were treated with palbociclib and aromatase inhibitor and 216 were treated with palbociclib and fulvestrant. The time-to-treatment discontinuation was 8.9 months in the case of P + f (95% CI: 7.1-12.7) and 13.7 months in the case of P + ia (95% CI: 8.9-17.5). In both cohorts, treatments that received at least one dose reduction had a statistically higher time-to-treatment discontinuation than those without dose reduction (17.7 months vs. 9.2 and 16.6 vs. 7.4).The mean adherence in our study was 0.9 and remained high in treatments with one dose reduction (0.83) and this with two dose reductions (0.87).
CONCLUSION: Based on these findings, it appears that the management of toxicities through reducing doses, as required by the Summary of Product Characteristics, results in a better outcome in terms of therapy duration, and therefore time to failure due to progression or toxicity.

Keywords: Palbociclib; breast cancer; real world; time-to-treatment discontinuation

DOI: https://doi.org/10.1177/10781552221117135

Pharmaceutics. 2022 Jun 21. pii: 1317. [Epub ahead of print]14(7):

Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer.

Perrine Courlet, Evelina Cardoso, Carole Bandiera, Athina Stravodimou, Jean-Philippe Zurcher, Haithem Chtioui, Isabella Locatelli, Laurent Arthur Decosterd, Léa Darnaud, Benoit Blanchet, Jérôme Alexandre, Anna Dorothea Wagner, Khalil Zaman, Marie Paule Schneider, Monia Guidi, Chantal Csajka.

Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic-pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils' time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies.

Keywords: neutropenia; palbociclib; pharmacokinetics; progression-free survival

DOI: https://doi.org/10.3390/pharmaceutics14071317

Int J Radiat Oncol Biol Phys. 2022 Jul 20. pii: S0360-3016(22)00725-8. [Epub ahead of print]

Radiotherapy with Cyclin-Dependent Kinase 4/6 Inhibitors: A Multi-institutional Safety and Toxicity Study.

Abdulla Al-Rashdan, Sarah Quirk, Michael Roumeliotis, Tasnima Abedin, Carla Paris Amaro, Lisa Barbera, Sasha Lupichuk, Jeffrey Q Cao.

PURPOSE: To investigate radiotherapy (RT) toxicity when given with Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) compared to RT alone.
METHODS AND MATERIALS: We conducted a retrospective cohort study of patients with hormonal receptor-positive and human epidermal growth factor-2 negative metastatic breast cancer treated with RT at four cancer centers in Alberta, Canada between 2016 and 2020. Toxicity in patients treated with RT within 30 days of initiating to discontinuing CDK4/6i (RT+CDK4/6i) was compared to toxicity of RT in CDK4/6i naïve patients (RT alone). The primary outcome was acute grade (G) II or higher, non-hematological toxicity within 30 days of RT. We also explored toxicity based on the timing of RT (prior, concurrent, post) in relation to CDK4/6i. Propensity score matching was applied to create comparable cohorts. A generalized linear mixed model was used to evaluate factors associated with acute toxicity.
RESULTS: 132 patients (220 RT sites) in the RT+CDK4/6i and 53 patients (93 RT sites) in RT alone were eligible. The rate of acute GII or higher non-hematological toxicity was 11.5% vs. 7%, respectively (p=0.439), and acute GIII or higher non-hematological toxicity was 3.7% vs. 0%, respectively (p=0.151). Acute toxicity in RT+CDK4/6i group was mainly observed when RT was given concurrently (67%) with most of the GIII toxicity recorded. After propensity score matching, the association of acute toxicity with RT+CDK4/6i vs. RT alone was not significant on multivariable analysis, Odds Ratio 3.13 (95% confidence interval: 0.74 - 13.2; p=0.121).
CONCLUSIONS: We did not observe a significant association between CDK4/6i use and acute, GII or higher, non-hematological toxicity, in women with metastatic breast cancer receiving palliative RT. Given the findings of GIII toxicity, caution is advised whenever CDK4/6i is given concurrently with RT.

DOI: https://doi.org/10.1016/j.ijrobp.2022.07.005