J. De Grève MD, PhD

O.10 USP13 as a novel co-target for EGFR targeted therapies in EGFR mutant non-small cell lung cancer

O.04 Type II RAF inhibition causes superior ERK suppression compared to type I RAF inhibition in different BRAF mutant types recurrently found in lung cancer

O.03 Identification of candidate breast cancer predisposition genes by sequencing extended panel of 492 cancer associated genes in BRCA1/2 negative probands

Parp inhibitors

Summary

Inhibition of Poly (ADP-ribose) polymerase 1 has relatively recently entered the clinic. The ground-breaking drug both scientifically and clinically was olaparib, but several other PARP inhibitors are in development. This treatment is the first to therapeutically exploit mutant recessive cancer genes. In this review we discuss the discovery of this treatment, the preclinical and clinical studies, as well as some future perspectives.

(BELG J MED ONCOL 2016;10(7):263–275)

Moving beyond the single agent targeting of activated pathways in cancer and emerging therapeutic targets in rare cancers

The ECC meeting is mostly focused on clinical results and some translational medicine. Nevertheless a couple of interesting developmental topics were presented.

Identification of primary drivers in all cancer types is moving along and treatments that match these genotypes are available or in development. One of the next challenges is to increase the initial efficacy of these treatments and overcoming secondary resistance. Indeed, all cancers treated with targeted agents, despite impressive results, ultimately become resistant due to secondary resistance mechanisms. In addition there is also something as “innate” resistance: the primary treatments do not achieve a maximal pathway shutdown and therapeutic efficacy. This is in part due to the pharmacological limitations of small molecules and monoclonal antibodies in the inhibition of the pathways they target. Hitting the same target with specific siRNA’s is generally more effective in shutting down the activated pathway. In addition, this innate resistance is also due to functional responsiveness of the cells that results in the activation of alternative pathways that dampen the effect of the primary treatment. Identification of these functional resistance mechanisms is important, as they would be candidate co-targets for primary targeted therapies. Another major void in our cancer armamentarium is the therapeutic exploitation of recessive cancer genes and tumor suppressor genes.

(BELG J MED ONCOL 2015;9:260–62)

Highlights in targeted therapy

In the previous decade major advances were made in targeted therapies as exemplified by the great progress in lung cancer. Today therapeutic innovation is dominated by the overwhelming breakthroughs in immunotherapy.¹ This is particularly great news as these novel immunotherapeutic drugs work best in those cancers in which our targeted therapies fail: cancers with many mutations. There is a strong emerging interaction between targeted therapies and immunotherapy and it appears that targeted therapies silence oncogenic pathways that promote immune tolerance. For example BRAF inhibition with vemurafenib leads to expansion of T-cells infiltrating melanoma, a prerequisite for response to PD1/PD-L1 immune checkpoint inhibitors.

(BELG J MED ONCOL 2015;9:154–7)

Therapy-orienting testing of BRCA1 and BRCA2 germline mutations in women with ovarian cancer

With the aim to optimally position poly-(adenosine diphosphate-ribose) polymerase inhibitors in the treatment of ovarian cancer, a panel of Belgian Experts came to a national multidisciplinary consensus: (i) germline BRCA1/2 testing should be indicated for all women with high-grade serous epithelial ovarian cancer, who are in good general condition (i.e. eligible for systemic treatment with low toxicity); BRCA1/2 mutation detection ratios being about 15–20% in this group; (ii) as the finding of a BRCA1/2 germline mutation has therapeutic implications in ovarian cancer patients, the request for therapy-orienting testing should be made as soon as possible during the course of first-line treatment. Pre-test genetic counselling is important because positive testing has implications for both the patients and their relatives, and the nature of the discussions depends on whether they take place in a therapeutic or familial context. The organisation of consultations should be coordinated in a collaborative effort between clinical geneticists, and gynaecological and medical oncologists, keeping in mind that ‘fast-track’ pre-test genetic counselling and short turnaround times are required for patients for whom the test results will have a therapeutic impact. Offering germline BRCA1/2 testing to all patients with high-grade serous epithelial ovarian cancer who are eligible for systemic treatment with low toxicity will lead to a limited increase in the number of patients eligible for this test in Belgium.

(BELG J MED ONCOL 2015;9(2):65–70)