Oncology Highlights - February 2016
Reading our newsletter will only take a few minutes and allows you to keep up to date with last month’s news items on oncology drug development.
Kind regards, the SMS-oncology team
Gabra3 gene in brain drives breast cancer metastasis
When breast cancer metastases, patient survival rates significantly drop, highlighting the need for identification of driver genes. Scientists from The Wistar Institute now have analyzed The Cancer Genome Atlas (TCGA) breast cancer data and identified 41 genes to be inversely correlated with survival, as published in Nature Communications. Of these, the GABAA receptor alpha3 (Gabra3) gene was of particular interest being normally exclusively expressed in adult brain tissue but found to be highly expressed in metastatic breast cancer (MBC). Gabra3 was demonstrated to activate the AKT pathway to stimulate breast cancer cell migration, invasion and metastasis. Interestingly, Gabra3 had undergone RNA editing (“A-to-I-edited Gabra3”) in non-invasive breast cancers thereby suppressing the AKT pathway activation and thus the spreading to other organs. These major findings indicate the importance of RNA editing in breast cancer for the first time, as well as targeting Gabra3 as potential treatment option. The latter has great potential since Gabra3 is a cell surface molecule allowing for drug targeting, further underlined by the fact that Gabra3 targeting drugs are already available for the treatment of other diseases such as insomnia. Read more >
Identification of 4 pancreatic cancer subtypes influences therapy possibilities
A recent publication in Nature shows evidence for the existence of four molecular pancreatic cancer subtypes, characterized by different genetic triggers and survival rates. By analyzing 456 pancreatic ductal adenocarcinomas, a team of Australian researchers was able to identify 10 genetic pathways involved in the transformation of normal pancreas tissue into cancerous forms: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Further analysis led to the definition of 4 pancreatic cancer subtypes: 1) squamous; 2) pancreatic progenitor; 3) immunogenic; and 4) aberrantly differentiated endocrine exocrine (ADEX) correlating with histopathological features. The significant results indicate better diagnosis and personalized therapy possibilities in the future. The latter is further strengthened by the notion that some of the mutations found to be driving pancreatic cancer development are unexpectedly associated with colon cancer or leukemia development, for which investigational drugs are already available or in development. Read more >
Refocus of NCI-60 cell line panel to fresh tumor cancer models
After being used by researchers all over the world for over 25 years, the US National Cancer Institute (NCI) has decided to retire its panel of 60 human cancer cell lines grown in culture (NCI-60) and start offering fresh tumor cancer models as of this year. This should meet the need to use models that are closer linked to the specific patients intended to benefit from the research. On the 11th of February, the American Association for Cancer Research (AACR) hosted a meeting about the creation of new cancer models from clinical samples. The NCI is currently developing hundreds of patient-derived xenografts (PDXs) by implanting small pieces of human tumors into mice, as this model better mimics the native environment. The NCI will distribute cells from these PDXs. In addition, the NCI will share data regarding the tumor’s genetics and gene expression patterns, as well as the donor’s treatment history. They will also produce cell lines from fresh patient samples for more detailed biochemical studies and drug screening purposes, cell lines that contain cultures of associated non-cancerous fibroblasts, as well as cell cultures and xenografts from circulating tumor cells (CTCs). The NCI will keep on supplying the NCI-60 cell lines for now. Read more >
No evidence that radiation from X rays and CT scans cause cancer
According to a study published in the American Journal of Clinical Oncology, the belief that radiation from X rays, CT scans and other medical imaging can cause cancer is based on an old theoretical model without evidence supporting it. The model known as linear no-threshold (LNT) is used to quantify radiation exposure and set regulatory limits, and assumes that there is a direct correlation between the dose of ionizing radiation with the long term, biological damage (basically the cancer risk) caused by it. However, the LNT model assumes that there is no safe dose of radiation, irrespective of how small the size; but it does not take into account the ability of the human body to repair damage from low-dose radiation naturally present in the environment. Dr. Welsh and colleagues from Loyola University Medical Center regard the LNT model to be causing unfounded fears and unnecessary costs on presumed but inefficient safety measures, and conclude that the LNT model should be abandoned. Read more >
EMA / FDA
EMA oncology drug recommendations for approval February 2016:
The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for:
- Lonsurf (trifluridine / tipiracil by Les Laboratoires Servier) for the treatment of adult patients with metastatic colorectal cancer (CRC) patients. The antineoplastic agent combined with a thymidine phosphorylase inhibitor interferes with DNA function and thereby prevents cell proliferation. Specifically, Lonsurf will be orally given to mCRC patients who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents.
- Palonosetron Hospira (palonosetron by Hospira UK Limited) for the prevention of nausea and vomiting associated with chemotherapy. It is a generic medicine of Aloxi, a drug that has been EMA approved in 2005. The API is palonosetron (as hydrochloride) and acts by blocking serotonin receptors and subsequently the neuronal cascade of events in which chemotherapy causes nausea and vomiting.
- Giotrif (afatinib by Boehringer Ingelheim) as monotherapy for the treatment of locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy. The tyrosine kinase inhibitor (TKI) targets epidermal growth factor receptor (EGFR) and erbB-2 (HER2). Giotrif has already been approved for EGFR TKI-naïve NSCLC patients with activating EGFR mutations.
- Opdivo (Nivolumab by Bristol-Myers Squibb) for the treatment of 1) locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adults (not restricted to squamous anymore; extension of indication), and 2) advanced renal cell carcinoma (RCC) after prior therapy in adults (adoption of new indication). The PD-1 inhibitor has previously already been approved for the treatment of advanced (unresectable or metastatic) melanoma in adults.
The FDA adopted an extension of indication for:
- Afinitor (everolimus by Novartis) for the treatment of adult patients with progressive neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. The mTOR inhibitor is already indicated for the treatment of various other cancers, including breast cancer and renal cell cancer.
- Gazyva (obinutuzumab by Genentech) for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen as a combination therapy with bendamustine, followed by obinutuzumab monotherapy. The monoclonal antibody that targets CD20 to kill B cells was previously approved for use in combination with chlorambucil for the treatment of chronic lymphocytic leukemia (CLL) treatment-naive patients.
- Ibrance (palbociclib by Pfizer) for the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer in combination with fulvestrant in women with disease progression following endocrine therapy. Last year, the kinase inhibitor was already granted accelerated approval in the same indication but then as combination therapy with letrozole as initial endocrine based therapy in postmenopausal women.
US cancer prevention guidelines fail in providing info required for decision-making
Considering the genetic heterogeneity and complexity of advanced cancers, screening as well as early detection and active preventive intervention are 2 major strategies to reduce the global cancer burden. For this reason, cancer prevention and screening intervention guidelines are made to provide clinicians with high-quality information on the benefit-harm ratio to help them make educated decisions regarding patient care. However, current US guidelines seem to be suboptimal according to a new study published in Journal of the National Cancer Institute. In this study 55 recommendations for using interventions to prevent or detect breast, prostate, colon, cervical, and lung cancer in 32 guidelines were analyzed. Of those 39% received a comparable rating, while 14.5% received an incomplete rating, and the remaining 54.5% received an asymmetric rating. The study included recommendations from the United States Preventive Services Task Force, the American Cancer Society, the American College of Physicians, the National Comprehensive Cancer Network, and other US guidelines within the National Guidelines Clearinghouse. The authors emphasize the need for improved guidelines thereby moving away from general concepts towards targeted approaches, e.g. individuals at high risk and on primary localized disease. Read more >