2. p53 mutations in 10,000 cancer patients shed
new light on gene's function
• One of the most extensively studied genes in cancer, TP53 is well known for its role as a
tumor suppressor. Researchers have conducted the most comprehensive study of TP53
mutations to better understand the processes leading to the inactivation of this
important gene. Their findings shed light on how the gene becomes mutated and how
those mutations can help predict clinical outlook.
• The team, led by Dr. Larry Donehower, professor of molecular virology and microbiology
at Baylor College of Medicine, studied 10,225 patient samples from 32 different cancers,
from The Cancer Genome Atlas, and compared them to another 80,000 mutations in a
database collected over three decades by Dr. Thierry Soussi, professor of molecular
biology at Sorbonne University. After analyzing this large data sample, they have a more
thorough understanding of how the TP53 gene mutation impacts cancer.
• The team found that across all cancer types studied, TP53 mutations were more frequent
in patients with poorer survival rates. But they also identified a way to more accurately
predict prognosis. Donehower said he identified four upregulated genes in mutant TP53
tumors, whose expression correlated to patient outcome.
3. p53 may play a more important role in kidney
cancer than previously thought
• The well-known cancer gene, p53, which researchers had thought was less
relevant in kidney cancer, may play an important role after all – a discovery that
could potentially lead to new treatments.
• A study conducted by researchers at Thomas Jefferson University suggests that
the second-most mutated gene in kidney cancer – PBRM1 - is strongly linked to
the inactivation of the p53 pathway. Since PBRM1 is also found in many other cell
types and cancers, the finding may have implications for other types of cancer.
• As reported in the journal Nature Communications, Yang and colleagues probed
genes that are known to be involved with kidney cancer for interactions with p53.
• The second most mutated gene in kidney cancer is the tumor suppressor PBRM1
and research has previously suggested that this gene may interact with p53.
However, so far, researchers have been unable to confirm whether this is an
important mechanism in kidney cancer.
4. Research into Tumor Suppressor P53 in
Ovarian Cancer Receives $1.8M NIH Grant
• A research team at the David Geffen School of Medicine at UCLA received a $1.8 million,
five-year grant from the National Institutes of Health (NIH) to develop new therapeutic
and preventive strategies for ovarian cancer based on the tumor suppressor p53.
The team, led by Alice Soragni, PhD, will focus on the role of p53 in cancer onset and
progression. It will also investigate the preventive effects of ReACp53, a p53-reactivating
molecule that has shown promise in fighting ovarian cancer in preclinical studies. P53 is
a natural tumor suppressor that cells use to prevent uncontrolled growth. It arrests cell
growth and promotes either DNA repair or cell death in cells with DNA damage or in
stressful environments such as low oxygen or low nutrients. It also plays an important
role in regulating several aspects of anti-tumor immune responses.
• Mutations in TP53, the gene that contains the instructions to produce the p53 protein,
block p53 anti-tumor function, leaving cells more susceptible to uncontrolled growth. A
fraction of these mutations results in a protein with an abnormal structure, which
promotes the formation of p53 aggregates, resulting in p53 inactivation. TP53 is the
most frequently mutated gene in human cancers — estimated to occur in over 50% of all
tumors — and mutations in this gene are usually associated with cancer resistance to
therapy and poor clinical outcomes. Currently, there are no approved therapies to
restore p53 function.
5. Cancer: These 4 genes help predict outcome
• Extensive research into the role of the tumor suppressor p53 offers a greater
understanding of the genetic mutations that are at play in various forms of cancer, as
well as identifying four genes that may help predict a person’s outlook.
• The TP53 gene is responsible for encoding what scientists call tumor protein p53 — a
tumor suppressor that can stop cells from dividing and proliferating too fast.
• Researchers have dubbed TP53 the “guardian of the genome” because of its crucial role
in preventing tumors and keeping cellular division in check.
• Human cancers frequently feature mutations in the TP53 gene, causing one of the critical
defensive mechanisms against cancer to fail.
• Now, , the largest study of its kind uses tumor samples from over 10,000 cancer patients
and looks at 32 different types of cancer to better understand the role of TP53.
• Dr. Larry Donehower, a professor of molecular virology and microbiology at the Baylor
College of Medicine in Houston, TX, led the new research, which appears in the
journal Cell Reports.
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8. A nanoparticle’s pathway into tumours
• New evidence now suggests that the dominant mechanism of
extravasation of nanoparticles into solid tumours may be through an
active process of endothelial transcytosis.
• The disruptive observations in this study provide a wake-up call to the
cancer nanomedicine community. It is time to revisit long-established
paradigms and embark on fundamental studies to increase our
understanding of each step in a nanoparticle’s road into a tumour,
since this is likely to be key to engineer cancer nanomedicines that
fulfil the promises of this field.
9. Novel anti-cancer nanomedicine for efficient
chemotherapy
• Researchers have developed a new anti-cancer nanomedicine for targeted cancer
chemotherapy. This new nano-tool provides a new approach to use cell-based
nanomedicines for efficient cancer chemotherapy.
• Exosomes contain various molecular constituents of their cell of origin, including
proteins and RNA. Now the researchers have harnessed them together with
synthetic nanomaterial as carriers of anticancer drugs. The new exosome-based
nanomedicines enhanced tumor accumulation, extravasation from blood vessels
and penetration into deep tumor parenchyma after intravenous administration.
• Nanoparticles-based drug delivery systems have shown promising therapeutic
effcacy in cancer. To increase their targettibility to tumors, nanoparticles are
usually functionalized with targeted antibodies, peptides or other biomolecules.
However, such targeting ligands may sometimes have a negative infuence on the
nanoparticle delivery owing to the enhanced immune-responses.
10. Targeted crystallization of mixed-charge
nanoparticles in lysosomes induces selective death
of cancer cells
• Lysosomes have become an important target for anticancer therapeutics because
lysosomal cell death bypasses the classical caspase-dependent apoptosis
pathway, enabling the targeting of apoptosis- and drug-resistant cancers.
However, only a few small molecules—mostly repurposed drugs—have been
tested so far, and these typically exhibit low cancer selectivity, making them
suitable only for combination therapies.
• Here, this study showed that mixed-charge nanoparticles covered with certain
ratios of positively and negatively charged ligands can selectively target
lysosomes in cancerous cells while exhibiting only marginal cytotoxicity towards
normal cells. This selectivity results from distinct pH-dependent aggregation
events, starting from the formation of small, endocytosis-prone clusters at cell
surfaces and ending with the formation of large and well-ordered nanoparticle
assemblies and crystals inside cancer lysosomes. These assemblies cannot be
cleared by exocytosis and cause lysosome swelling, which gradually disrupts the
integrity of lysosomal membranes, ultimately impairing lysosomal functions and
triggering cell death.
11. A Microfluidic Platform to design Multimodal PEG -
crosslinked Hyaluronic Acid Nanoparticles (PEG-
cHANPs) for diagnostic applications
• The combination of different imaging modalities can allow obtaining simultaneously
morphological and functional information providing a more accurate diagnosis. This
advancement can be reached through the use of multimodal tracers, and
nanotechnology-based solutions allow the simultaneous delivery of different diagnostic
compounds moving a step towards their safe administration for multimodal imaging
acquisition.
• Among different processes, nanoprecipitation is a consolidate method for the production
of nanoparticles and its implementation in microfluidics can further improve the control
over final product features accelerating its potential clinical translation. A Hydrodynamic
Flow Focusing (HFF) approach is proposed to produce through a ONE-STEP process
Multimodal Pegylated crosslinked Hyaluronic Acid NanoParticles (PEG-cHANPs). A
monodisperse population of NPs with an average size of 140 nm is produced and Gd-
DTPA and ATTO488 compounds are co-encapsulated, simultaneously.
• The results showed that the obtained multimodal nanoparticle could work as
MRI/Optical imaging probe. Furthermore, under the Hydrodenticity effect, a boosting of
the T1 values with respect to free Gd-DTPA is preserved.
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