Clinical Oncology

[Cell cycle as therapeutic target – CDK4/6 inhibition]


FEBRUARY 10, 2017

Clinical Oncology - 2017;4(01)

[One of the most important decision of a cell: to live or die. If survival is the choice, there are three options: proliferate, to stay in sleeping state for a while, or differentiate in order to perform its specifi c function. These decisions are under a very strict molecular regulation infl uenced by internal and external factors. Tumor cells more and more disregard the regulations, and move into independency for a continuous proliferation, which has a very similar program in normal and tumor cells. The main route towards mitosis is the cell cycle, under the supervision of positive and negative regulators, forming checkpoints, telling to the cell - under the infl uence of mitogenic signals - to go or to stop. The most critical checkpoint is at the border of G1 and S phases where the main players are cyclinD, CDK4/6 and RB1. It turned out that the best targets to inhibit cell proliferation are the CDKs, but this approach, when used unselected targets, was unsuccessful due to the toxicity. To improve the clinical results, the selection of CDK4/6 as a therapeutic target seems to fulfi l most of the hopes. Today three drugs are the most promising: palbociclib (with an acceptance by FDA and EMA to treat breast cancer patients), abemaciclib and ribociclib (underclinical trials). Now, most of the data concern breast cancer, especially the combinations of CDK4/6 inhibitors and endocrine therapy, but many other malignancies are studied (e.g. liposarcoma, mantel cell lymphoma, melanoma, renal cancer, lung cancer, pancreatic cancer, ovarian cancer, teratomas etc.). The key points are the side-effects, the most frequently observed is neutropenia, but so far it is managed without serious toxicity.]



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[The majority of patients with diffuse large B-cell lymphoma can be cured using the standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) based therapy. However, approximately 30-40% of the patients are refractory to the therapy or they relapse. The currently available salvage therapies represent a realistic curative approach only for approximately one quarter of the patients. Therefore, there is unmet clinical need for more effi cient fi rst line and salvage therapies in DLBCL. The rapid advances in the fi eld of molecular genetic techniques lead to a better understanding of the biological heterogeneity as well as the discovery of the key factors involved in the pathogenesis of the disease. Nowadays, the distinction between the cases with germinal center B-cell and activated B-cell origin characterized with different prognosis has therapeutic implications. Presently, the therapy of the so-called double-hit lymphomas also represents an unmet clinical need. The next generation sequencing based studies lead to the discovery of novel molecular targets, including components of different cellular signaling pathways, immune checkpoints and components of the microenvironment. Targeted therapies against many of these molecular targets are being tested in different clinical trials. Due the heterogeneity of the disease, it is of critical importance to identify those patient groups who will benefi t from a particular targeted therapy. Hopefully, this risk-adopted therapeutic approach will become soon available for patients with DLBCL. Currently, the R-CHOP therapy still represents the gold standard in treatment of patients with DLBCL.]

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[Systemic therapy (ST) (including chemotherapy, targeted therapy, and immunotherapy) or radiation therapy (RT) can induce gastrointestinal side effects, which frequently affect patient’s quality of life. Sometimes side effects could be dose-limiting, or a reason to stop the treatment. The incidence and severity of gastrointestinal complications in patient’s receiving ST, RT, or chemoradiotherapy are affected by numerous factors, including: therapeutic agents, doses and route of administration, target of the RT (upper, lower abdomen or body) and individual patient variability (age, sex, prior cancer therapy, comorbidities, performance status). Mucositis occurs in approximately 20% to 40% of patients receiving conventional chemotherapy, 80% of patients receiving high-dose chemotherapy, nearly all patients receiving head and neck radiation therapy. mTOR inhibitor-associated stomatitis (mIAS) is the most frequent dose-limiting toxicity (52.5%). More than 90% of patients receiving highly emetogenic chemotherapy will have episodes of vomiting. However, only about 30% of these patients will vomit if they receive prophylactic antiemetic regimens.]

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[During chemoradiotherapy the two main non-surgical anticancer methods are combined to improve the treatment outcomes. The theoretical possibilities of interactions and the most frequently used drugs will be presented here, emphasizing that although both the radiation therapy and the drugs need to be administered in full dose in practice considering the summarization of side effects we often have to make compromises. The treatments of the most frequent indications (brain, head and neck, oesophagus, lung, stomach, pancreas, rectum, bladder, cervix, soft tissue sarcoma) will be demonstrated. Since there are several drugs and drug combinations that are not included in the Hungarian registered anticancer therapies, for their off-label use the permission of the National Institute of Pharmacy and Nutrition is required. To choose the optimal treatment (during planning the optimal place of chemoradiotherapy, agents and doses) the opinion of a multidisciplinary team is necessary]

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