An article published in a recent issue of The Journal of Experimental Medicine, by researchers at Queen Mary, University of London (London, UK), has shown that upregulation of TP63 can lead to chemoresistant melanoma.
Melanoma, which is mainly caused by overexposure to UV light, has the fastest-rising number of cases for any cancer despite being one of the less common forms of skin cancer. Melanoma makes up approximately 5% of skin cancers and yet accounts for over 75% of skin cancer-related deaths.
Scientists at Queen Mary, University of London (London, UK) have been investigating the molecular role of apoptosis in melanoma pathogenesis, in addition to why certain tumors gain chemoresistance. The p53 (TP53) apoptotic pathway is deregulated in the majority of melanomas, despite mutations in TP53 being infrequent. Surprisingly the group discovered that the master gene of epithelial development, TP63, which is almost undetectable in primary melanocytes, was upregulated in melanoma cell lines.
Daniele Bergamaschi, a senior lecturer in cutaneous research at Queen Mary, University of London and one of the authors of the paper, explained to Pharmacogenomics that “When melanoma cells are exposed to DNA-damaging agents such as UV radiation or chemotherapeutic drugs, p63 is stabilized –so its expression is increased –in the nucleus and translocates to the mitochondria where it causes apoptotic resistance; prevents the melanoma cells from being killed.” Bergamaschi continued, “Our data provides evidence of a physiological interaction between p63 and p53 whereby p63 inhibits p53‘s ability to induce apoptosis.”
Bergamaschi described the link between TP63 expression and poor prognosis in melanoma patients, saying “The expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Analysis of the p63-positive population demonstrated a significant association with the Breslow‘s thickness of primary melanoma, a positive trend towards shorter time to recurrence and to metastases. Moreover, individuals with p63-postive primary and metastatic tumors had significantly worse disease-specific outcomes.”
This discovery explains why some melanoma cells do not undego apoptosis, even when they are exposed to chemotherapuetic drugs, and will hopefully lead to the development of new treatments. Bergamaschi continued, “As a matter of fact, silencing of P63 sensitizes the ability of melanoma cells to die from apoptosis once exposed to DNA damage, including the promising new BRAF inhibitor, vemurafenib, which is currently in use for melanoma treatment.”
Beramaschi concluded, “We therefore suggest that p63 should be considered when designing new treatments for melanoma that are focused on reactivating the apoptotic pathway in order to make the cancer cells easier to kill.”
Sources: Matin RN, Chikh A, Law Pak Chong S et al. p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis. J. Exp. Med. 210(3), 581–603 (2013); Queen Mary Press release: www.qmul.ac.uk/media/news/items/smd/90919.html
A study presented at the recent 2013 Gastrointestinal Cancers Symposium (CA, USA) has shown that pharmacogenomic profiling of tumor progenitor cells allows for a more effective treatment regimen in pancreatic cancer.
Pancreatic adenocarcinoma is a uniformly lethal type of cancer, however, there are cytotoxic compounds that can prevent tumor growth and extend a patient‘s life expectancy. Currently, physicians cannot identify which pancreatic tumors will respond to which drugs without using trial and error. Researchers from the Memorial Sloan–Kettering Cancer Center (NY, USA) presented their preliminary results from a clinical trial where a gene profile and cytotoxic analysis was taken for pancreatic tumor progenitor cells to help predict the most effective treatment.
A peripheral blood sample of 10 ml was collected and circulating tumor progenitor cells were isolated for 46 enrolled pancreatic cancer patients. These were analyzed for gene expression and chemosensitivity to 12 chemotherapy drug combinations.
Kenneth Yu, who presented the research, explained, “Now that we have a number of effective chemotherapy choices, one major problem that remains is that we do not have a validated biomarker, a way to help us, as treating physicians, to choose effective treatment for patients that we see.”
Data were presented from the first 20 patients and showed that individuals who were predicted as having treatment-susceptible profiles had a median progression time that was twice the length of patients who were identified as having resistant tumors; 7.3 compared with 3.7 months.
In addition, the genetic analysis identified a number of gene pathways that had an association with treatment response; disruptions to the E2F1 and NF-κB pathways cause a longer and shorter duration treatment response, respectively.
“The bottom line is that patients receiving treatment predicted by our model to be more effective did better,” said Yu.
The results show that cytotoxic profiling can predict treatment outcome for pancreatic cancer patients. Yu concluded, “There is still a lot of work that needs to be done to prove that this is effective, but the goal would be to have the blood drawn, have the profiling done, figure out which combinations of drugs are most effective for the patient, and start with those drugs, as opposed to the way we normally do it now (trial and error).”
Sources: Sangar V, Ricigliano M, O‘Reilly EM et al. Use of pharmacogenomic modeling in pancreatic cancer for prediction of chemotherapy response and resistance. J. Clin. Oncol. 30(Suppl. 34), Abstract 142 (2012); Medpage today news article: www.medpagetoday.com/MeetingCoverage/MGICS/36971
A paper recently published in Nature Communications has identified FBHI as an essential gene for some chemotherapeutic drugs to work.
Researchers from the Biotech Research and Innovation Centre (BRIC) and Center for Healthy Aging, University of Copenhagen (Copenhagen, Denmark) used RNAi to knockout specific genes in tumor cells to see how this would alter the effect of chemotherapeutic drugs.
“By using the method to remove single genes from cancer cells and then exposing the cells to chemotherapy, we found that FBH1 is important for the effect of the chemotherapy,” explained Kasper Fugger, one of the authors of the paper. “Actually, the presence of the gene was an absolute requirement in order to effectively kill the cancer cells with the type of chemotherapeutics we have studied.”
FBH1 codes for a helicase that mediates DNA double-strand break formation following replication inhibition. The group discovered that FBH1-deficient tumor cells were resistant to the replication inhibitor, hydroxyurea, which additionally supported their findings. The group also found that MUS81 and EME1 cooperated with FBH1 and are required to eliminate cells with excessive replication stress.
Claus S⊘rensen, Associate Professor at the University of Copenhagen and leader of the team, said, “Our results could help indicate that patients with low or no FBH1 in cancer cells will not benefit from certain types of chemotherapy, but should be administered with another type of treatment. By using the genetic fingerprint of a tumor, doctors can adjust the treatment to individual patients.”
The identification of FBH1 as an essential enzyme in inducing cell death makes it a novel target for new therapeutic drugs. Nonsense mutations in FBH1 grant tumor cells resistance to chemotherapy so the development of a therapy that increased the effect of FBH1 helicase would make cancers more sensitive to treatment.
Fugger described how these results may lead to new ways to treat cancer, saying, “Our hope is to find a method to boost the activity of the FBH1 gene in cancer cells since this will make them more sensitive to chemotherapy. Alternatively, we may find a way to simulate an effect similar to that of FBH1, which can be used as additional treatment in order to sensitize cancer cells to chemotherapy. If we achieve this, more patients will benefit from the treatment.”
S⊘rensen concluded “Our results show that the FBH1 gene is crucial in order for some chemotherapeutics to become active in the body and kill the cancer cells. If we can find a feasible method to increase the activity of the gene, we can use our cells‘ own resources to improve cancer treatment.”
Source: Fugger K, Kit Chu W, Haahr P. FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. Nat. Commun. 4, 1423 (2013).
–All stories written by Theo Bond
A group at the The Ohio State University (OH, USA) have identif polymorphisms in two genes, DAT and DRD, that have an association with an increased risk of fatal cocaine intoxication.
The paper, recently published in Translational Psychiatry, suggested that SNPs in DAT and DRD2 were associated with an approximately eightfold increased risk of mortality from cocaine abuse. The group approximated that one-third of all white individuals (Caucasian and Hispanic) who died from cocaine abuse were carriers of variants of these genes.
DNA was extracted from the brain tissue of 126 individuals, who had died owing to cocaine intoxication, and compared with 99 age-matched control subjects (nondrug-related death). In addition, the group also looked at the associations of genetic variants with the different ethnicities of the subjects. A total of 143 subjects were white, 81 were African–American and one from the Pacific Isles.
When speaking to Pharmacogenomics, Wolfgang Sadee, Director of the program in pharmacogenomics at The Ohio State University, described previous research that had identified “splice variants in DRD2, generating short and long D2 proteins (D2S and D2L), were found to be associated with a two- to three-fold increased risk of death in heavy cocaine abusers.”
“We determined that a combination of one variant in each DRD2 and DAT epistatically interact with each other to drive the lethal risk to a factor of seven to eight,” Sadee explained. “Because of large ethnic differences in allele frequency, this SNP combination was prevalent only in white patients, whereas in African–Americans, a DAT haplotype carrying two regulatory variants proved a strong predictor of lethal risk.”
DRD2 codes for a dopamine receptor that is targeted by a number of antipsychotic drugs, including chlorpromazine and haloperidol. “The altered functions of these proteins were found to be associated with clinical phenotypes, such as cognitive processing for DRD2 and risk of bipolar disorder for DAT,” Sadee concluded. “It is now imperative to determine how DRD2–DAT interactions determine other disease phenotypes and outcomes, for example stimulant therapy of attention-deficit/hyperactivity disorder.”
Source: Sullivan D, Pinsonneault JK, Papp AC et al. Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene–gene–environment interaction. Transl. Psychiatry 3, e222 (2013).