The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.

Cancer genes and the pathways they control.

Links between human papillomaviruses (HPVs) and cervical cancer were first suspected almost 30 years ago. DNA of specific HPV types has since been found in almost all cervical cancer biopsies. HPV oncogenes that are expressed in these cells are involved in their transformation and immortalization, and are required for the progression towards malignancy. Epidemiological studies have underlined that HPVs are the main aetiological factor for cervical cancer. But how has this knowledge been translated into the clinic to allow the prevention, screening and treatment of cervical cancer?

http://www.hu.ufsc.br/projeto_hpv/Papillomavirus%20and%20cancer.pdf

Papillomaviruses and cancer: from basic studies to clinical application

Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.

Cell cycle, CDKs and cancer: a changing paradigm

A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis ('cancer genes'). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a 'census' of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes.

A census of human cancer genes

ContextMore persons in the United States die from non–small cell lung
cancer (NSCLC) than from breast, colorectal, and prostate cancer combined.
In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors
that express the epidermal growth factor receptor (EGFR), a mediator of cell
signaling, and phase 1 trials have demonstrated that a fraction of patients
with NSCLC progressing after chemotherapy experience both a decrease in lung
cancer symptoms and radiographic tumor shrinkages with gefitinib.ObjectiveTo assess differences in symptomatic and radiographic response among
patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib.Design, Setting, and PatientsDouble-blind, randomized phase 2 trial conducted from November 2000
to April 2001 in 30 US academic and community oncology centers. Patients (N
= 221) had either stage IIIB or IV NSCLC for which they had received at least
2 chemotherapy regimens.InterventionDaily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib
tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching
placebo).Main Outcome MeasuresImprovement of NSCLC symptoms (2-point or greater increase in score
on the summed lung cancer subscale of the Functional Assessment of Cancer
Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion
size on imaging studies).ResultsOf 221 patients enrolled, 216 received gefitinib as randomized. Symptoms
of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients
receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving
500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial
radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving
250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg.
Symptoms improved in 96% of patients with partial radiographic responses.
The overall survival at 1 year was 25%. There were no significant differences
between the 250-mg and 500-mg doses in rates of symptom improvement (P = .26), radiographic tumor regression (P = .51), and projected 1-year survival (P =
.54). The 500-mg dose was associated more frequently with transient acne-like
rash (P = .04) and diarrhea (P = .006).ConclusionsGefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved
disease-related symptoms and induced radiographic tumor regressions in patients
with NSCLC persisting after chemotherapy.

https://jamanetwork.com/journals/jama/articlepdf/197532/JOC31026.pdf

Efficacy of Gefitinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Symptomatic Patients with Non-Small Cell Lung Cancer: A Randomized Trial

Although KIT-mutant GISTs can be effectively treated with tyrosine kinase inhibitors (TKIs), many patients develop resistance to imatinib mesylate (IM) as well as the FDA-approved later-line agents sunitinib, regorafenib and ripretinib. Resistance mechanisms mainly involve secondary mutations in the KIT receptor tyrosine kinase gene indicating continued dependency on the KIT signaling pathway. The fact that the type of secondary mutation confers either sensitivity or resistance towards TKIs and the notion that secondary mutations exhibit intra- and intertumoral heterogeneity complicates the optimal choice of treatment in the imatinib-resistant setting. Therefore, new strategies that target KIT independently of its underlying mutations are urgently needed. Homoharringtonine (HHT) is a first-in-class inhibitor of protein biosynthesis and is FDA-approved for chronic myeloid leukemia (CML) that is resistant to at least two TKIs. HHT has also shown activity in KIT-mutant mastocytosis models, which are intrinsically resistant to imatinib and most other TKIs. We hypothesized that HHT could be effective in GIST through downregulation of KIT expression and subsequent decrease of KIT activation and downstream signaling. Testing several GIST cell line models, HHT led to a significant reduction in nascent protein synthesis and was highly effective in the nanomolar range in IM-sensitive and IM-resistant GIST cell lines. HHT treatment resulted in a rapid and complete abolishment of KIT expression and activation, while KIT mRNA levels were minimally affected. The response to HHT involved induction of apoptosis as well as cell cycle arrest. The antitumor activity of HHT was confirmed in a GIST xenograft model. Taken together, inhibition of protein biosynthesis is a promising strategy to overcome TKI resistance in GIST.

/pdf/targeting-the-translational-machinery-in-gastrointestinal-2ve8v55ino.pdf

Anette Duensing

Papers

Targeting the translational machinery in gastrointestinal stromal tumors (GIST) - a new therapeutic vulnerability