npj Precision Oncology 2017 wrap-up
Here are the editorial summaries for our 2017 original research articles. Enjoy!
Diagnosis, prognosis, and therapeutic and risk factors
Breast cancer patients do better after preoperative chemotherapy if their numbers of circulating endothelial progenitor cells (CEPs) go up. A team from Japan led by Takayuki Ueno from the Kyorin University School of Medicine in Tokyo studied 57 women who underwent neoadjuvant chemotherapy to shrink the size of their tumors before surgery. The researchers measured the number of CEPs—cells that derive from the bone marrow and can help build new blood vessels around tumors—both before and during chemotherapy. They found no link between overall CEP counts and treatment response. However, patients whose CEP numbers went up between cycles of chemotherapy had better outcomes. The authors suggest that CEP counts could be used as a diagnostic tool for predicting responses to neoadjuvant chemotherapy, although larger studies are needed to confirm their initial findings.
Gastric tumors often harbor a chromosome abnormality that disrupts a key signaling gene, resulting in less aggressive cancers. Oi Lian Kon from the National Cancer Centre Singapore and colleagues searched for chromosomal rearrangements in 17 gastric cancer cell lines. The researchers discovered a recurrent breakpoint in six of the cell lines that mapped to a gene called DOK6, which encodes a protein that provides a docking platform for multiple signaling molecules. They also found the abnormality in 22 of 99 tissue samples taken from gastric cancer patients. This defect led to lower expression of DOK6 and, in turn, less active oncogenic signaling pathways. Patients with low DOK6-expressing gastric cancers lived longer on average than those with high DOK6-expressing tumors. The findings point to DOK6 levels as a potential drug target and diagnostic biomarker.
A microfluidic device can rapidly and efficiently isolate circulating tumor cells from the blood of prostate cancer patients. Elodie Sollier-Christen of Vortex Biosciences, Rajan Kulkarni of David Geffen School of Medicine at UCLA, Dino Di Carlo of UCLA and colleagues tested the company’s microfluidic technology on blood samples taken from 21 men with advanced prostate cancer and 10 healthy controls. They showed that, within an hour, the Vortex Chip could isolate circulating tumor cells in 80% of the cancer patients and that many of these cells did not display the usual surface markers that other approaches require to capture prostate cancer cells. The purities and DNA yields of the isolated cells were high enough to enable targeted genome sequencing, which revealed mutations potentially involved in tumor formation. The Vortex technology could help diagnose prostate cancer and inform therapeutic decision-making for those with the disease.
Using two selection markers, instead of one, can improve the sensitivity of a blood test for circulating tumor cells (CTCs). Steven A. Soper from the University of Kansas in Lawrence, USA, and colleagues analyzed blood samples from patients with cancers of the pancreas, colon, breast, ovaries and prostate, as well blood from healthy donors and those with benign disease. They ran each patient’s blood through two microfluidic devices, one chip targeting the established marker epithelial cell adhesion molecule (EpCAM) and another targeting a new marker, fibroblast activation protein alpha (FAPα). Doing so detected CTCs in nearly all the cancer patients—a substantial improvement over testing for EpCAM CTCs alone. Molecular and genetic analyses of the CTCs showed that those expressing EpCAM and FAPα are distinct subpopulations, and testing for both could prove valuable for clinical management.
Higher consumption of “good fats,” or their natural creation by the body, may help protect people from colon cancer. Jian-Min Yuan from the University of Pittsburgh, USA, and colleagues used samples from the Singapore Chinese Health Study to examine fatty acids contained in blood plasma from 350 people who later developed colorectal cancer and an equal number of matched control individuals. They found that higher blood levels—which reflect dietary intake—of the essential polyunsaturated fatty acids linolenic acid and α-linolenic acid were associated with a lower risk of colon cancer. So was oleic acid, a monounsaturated fat created by the body, whereas conversion of linolenic acid to another fatty acid called arachidonic acid boosted colon cancer risk. No effect was seen on rectal cancer risk. Diets rich in linolenic acid may help prevent colon cancer.
Novel therapeutics and targets
The identification of a signaling pathway connected to the progression of breast cancer could prove a valuable therapeutic target. The breast cancer treatment tamoxifen, although successful, is limited to certain tumor types, and so the search is on to pinpoint molecular targets that are ubiquitous across breast cancers. Zigang Dong at the University of Minnesota, US, and co-workers identified that the thromboxane A2 (TXA2) pathway is highly-expressed in human breast tumors and premalignant lesions. Further examination showed that TXA2 is crucial for tumor cell growth and metastasis. When the researchers knocked-out TXA2 production in mouse models, this suppressed both the formation and spread of tumors. The team advise caution because TXA2 is also required for wound healing and other key processes, although short-term bursts of pathway suppression may be an option for breast cancer therapy.
Blocking an enzyme involved in the cellular synthesis of essential compounds called polyamines could help treat esophageal cancer. Zigang Dong from the University of Minnesota’s Hormel Institute, USA, and colleagues showed that this enzyme, called ornithine decarboxylase (ODC), is expressed at elevated levels in tumor tissues taken from patients with esophageal squamous cell carcinoma. The researchers blocked ODC activity in esophageal cancer cells using either RNA interference techniques or a drug called difluoromethylornithine (DFMO). In both cases, the treatment suppressed further growth and induced cell death. DFMO treatment also reduced the size and weight of tumors in mice implanted with human patient-derived esophageal cancer tissue. The findings point DFMO, which is already used as a medication to treat African sleeping sickness and excessive hair growth, as a potential therapy for cancer patients.
Combinations of two molecules found naturally in edible plants synergistically help reduce tumor growth in a mouse model of prostate cancer. Stefano Tiziani and John DiGiovanni from the University of Texas at Austin, and colleagues screened a library of 142 natural compounds for the effects of each molecule, alone or in combination, on the viability of cells from mouse and human prostate cancer cell lines. Amongst other promising combinations, the researchers identified ursolic acid and curcumin as the most promising combination for inhibiting tumor growth. (These compounds are found naturally in apple peels and turmeric, respectively.) In mice with implanted prostate tumors, the two compounds synergistically reduced tumor volume and weight, while in cell culture the researchers showed that the compound-combination strategy modulated metabolism of a critical amino acid and other cell signaling pathways.
Silver-coated gold nanorods deliver drugs to a difficult-to-treat breast cancer by targeting an over-expressed antigen on its surface. Ruud Dings and colleagues at the University of Arkansas in the USA loaded the chemotherapeutic drug doxorubicin onto silver-coated gold nanorods that were conjugated with an antibody that specifically targets an over-expressed antigen on many types of ‘triple-negative breast cancers’ (TNBCs). Unlike other breast cancers, TNBCs lack certain receptors, making them difficult to target with cancer therapies. The team found that one of the two TNBC cell lines studied over-expressed the epithelial antigen EpCAM 100 times more than the other. Their drug-loaded silver-coated gold nanorods specifically targeted the EpCAM over-expressing cells over the low-expressing ones. The nanorods’ coatings also allowed them to be easily detected by two different imaging techniques: surfaced-enhanced Raman spectroscopy and photoacoustic microscopy.
GBM is the most common and aggressive type of malignant primary brain tumors (glioma). Patients with GBM have less than 5% survival at 5 years with the best existing treatment and progress is desperately needed to improve patient outcome. Imaging can guide development and clinical translation of new treatments, and can help to understand mechanisms of response and to optimize drug regimens in patients. AA therapy that targets the blood supply of tumors can benefit GBM patients as adjuvant therapy to standard chemoradiation, but the timing of combination therapy may be important to obtain the maximum benefit and minimize negative side effects. Tracking metabolic changes with magnetic resonance spectroscopic imaging (MRSI) during a phase II clinical trial of AA drug cediranib combined with chemoradiation shows that there is a therapeutic window within the first month where there is maximal synergy between the effects of the anti-angiogenesis and chemoradiation. Our data suggest that adjusting the dose of AA therapy during chemoradiation may be beneficial, and MRSI can be used as a precision medicine tool to identify the patients and time for adjusting the combination treatment.
Cancer development, tumor growth, and drug resistance
Carboplatin efficacy can be restored by administering it with birinapant, a drug combination that targets platinum-resistant cancer cells. Platinum-based chemotherapeutics are used to treat almost 50% of cancer patients. Despite excellent initial response rates, tumor growth recurs in most patients as they develop resistance to therapy. Sanaz Memarzadeh and colleagues at the University of California, Los Angeles, show that the addition of birinapant to carboplatin eliminates platinum-resistant ovarian cancer cells by degrading the cell death-inhibiting proteins cIAP1 and cIAP2. Carboplatin and birinapant co-therapy restored the efficacy of the chemotherapeutic in human tumor samples and in mice with platinum-resistant tumors. Furthermore, the levels of cIAP protein in the resistant cells were predictive of the therapeutic response. These findings will help to select clinical trial patients that are most likely to benefit from this combination therapy.
Non-coding and structural alterations may be early drivers of brain cancer development. A team led by Priscilla Brastianos and Tracy Batchelor from Massachusetts General Hospital, Boston, USA, analyzed the genetic landscape of glioblastoma by comparing pre-treatment and autopsy tumor specimens from 12 patients who died of the aggressive brain cancer. They identified a common set of four genetic events that occurred early in the evolution of nearly every patient’s cancer: three losses or gains of chromosome regions or entire chromosomes, and mutations in the gene-activating promoter of TERT, which encodes an enzyme implicated in the cancer’s growth. The findings help explain why therapies that target protein-coding mutations don’t work in brain cancer when they do in other tumor types. They also point to new drug targets.
Skin exposure to ultraviolet radiation leads to the activation of proteins involved in carcinogenic pathways. Janine Einspahr and Clara Curiel-Lewandrowski of the Arizona Cancer Center and colleagues in the US exposed normally ultraviolet protected skin of 12 individuals to two times the dose of solar-simulated light needed to induce redness. Skin biopsies were taken before and after exposure and 128 proteins known to be involved in key cancer signaling pathways were examined using ‘reverse phase protein microarray analysis’. They found early and sustained activation of multiple signaling pathways, in addition to activation of cell death and apoptosis-related proteins. The study may serve as a model for investigating the pathways involved in chronic or ultraviolet-induced carcinogenesis, which may ultimately lead to the development of targeted therapies to attenuate or reverse skin cancer pathways.