Stanford U. Researchers Fire Potent Shot Across the Bow of Solid Tumour Cancers

A single drug can shrink or cure human breast, ovary, colon, bladder, brain, liver, and prostate tumors that have been transplanted into mice, researchers have found. The treatment, an antibody that blocks a "do not eat" signal normally displayed on tumor cells, coaxes the immune system to destroy the cancer cells. _ScienceMagNews

In research published on PNAS (Full PDF), Stanford researchers demonstrated the ability to successfully destroy human cancer growing in mice, using monoclonal antibodies targeted against the cellular protein CD47.

CD47 is overexpressed in many cancers, and allows the tumour cells to "fly beneath the immune system's radar," thus escaping destruction. By blocking CD47, the scientists demonstrated that the immune system was able to destroy tumour cells that would have been otherwise ignored.

To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was present, the macrophages engulfed and destroyed cancer cells from all tumor types.

Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment -- colon cancers transplanted into the mice shrank to less than one-third of their original size, on average. And in five mice with breast cancer tumors, anti-CD47 eliminated all signs of the cancer cells, and the animals remained cancer-free 4 months after the treatment stopped.

"We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis," says Weissman.

Although macrophages also attacked blood cells expressing CD47 when mice were given the antibody, the researchers found that the decrease in blood cells was short-lived; the animals turned up production of new blood cells to replace those they lost from the treatment, the team reports online today in the Proceedings of the National Academy of Sciences.

Cancer researcher Tyler Jacks of the Massachusetts Institute of Technology in Cambridge says that although the new study is promising, more research is needed to see whether the results hold true in humans. "The microenvironment of a real tumor is quite a bit more complicated than the microenvironment of a transplanted tumor," he notes, "and it's possible that a real tumor has additional immune suppressing effects."

Another important question, Jacks says, is how CD47 antibodies would complement existing treatments. "In what ways might they work together and in what ways might they be antagonistic?" Using anti-CD47 in addition to chemotherapy, for example, could be counterproductive if the stress from chemotherapy causes normal cells to produce more CD47 than usual. _SciencemagNews

This approach would probably not qualify as a solo therapy, but would rather be used along with other anti-cancer therapies, to either cure a cancer or to limit its growth and spread where cure is not possible.

Researchers believe that all solid tumours may well be vulnerable to this approach.

This treatment will not be without side effects, and not all cancer patients would benefit or qualify for such treatment. But it is very promising.

H/T NextBigFuture

Another Approach to Treating Alzheimer's In Early Stages

A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer's disease (AD). The results establish how the drug might be used in early-stage AD patients.

...EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.

After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What’s more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage -- in the transgenic mice that received EpoD. _UPennNews

Most approaches to treating Alzheimer's dementia aim to either affect the levels of neurotransmitters in the brain -- particularly acetylcholine -- or to decrease accumulation of amyloid beta protein.

The idea of over-stabilising neurotubules to prevent tau tangles from forming in early stage Alzheimer's is an intriguing approach, and dates to earlier studies attempting to discover the true etiological origins of Alzheimer's. More from a 2011 study published in The Journal of Neuroscience:

Alzheimer's disease (AD) pathology is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs) (Selkoe, 2001). SPs are extracellular deposits of amyloid-β (Aβ), a 3–4 kDa peptide derived from proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP cleavage enzyme 1 (BACE) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999) and the presenilin (PS)-containing γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999). NFTs are intracellular accumulations of hyperphosphorylated tau (Lee et al., 2001). About 5% of AD cases are linked to pathogenic mutations in APP, PS1, or PS2 genes (Selkoe, 2001). Tau gene mutations are pathogenic for familial frontotemporal lobar degeneration characterized by tau pathology without SPs, indicating that tau abnormalities alone cause neurodegenerative disease (Lee et al., 2001). _Journal of Neuroscience 25 May 2011, 31(21): 7691-7699; doi: 10.1523/​JNEUROSCI.6637-10.2011

Note that researchers are still attempting to unravel the apparent multiple strings of causation involved in Alzheimer's Disease (AD) and similar neurodegenerative diseases of the brain.

The new research involving microtubule stabilisation, was performed in transgenic mice, meaning that results in human populations using such treatments may be quite different. The fact that both amyloid placques and tau tangles are seen in pathological brain specimens from AD patients suggests that more than one treatment approach may ultimately be required for many, if not most AD sufferers.

Cross-posted from Al Fin blog

Progress on Two Important SENS Anti-Ageing Themes

Aging Damage	Discovery	SENS Solution
Cell loss, tissue atrophy	19551	Stem cells and tissue engineering (RepleniSENS)
Nuclear [epi]mutations (only cancer matters)	19592, 19823	Removal of telomere-lengthening machinery (OncoSENS)
Mutant mitochondria	19724	Allotopic expression of 13 proteins (MitoSENS)
Death-resistant cells	19655	Targeted ablation (ApoptoSENS)
Tissue stiffening	19586, 19817	AGE-breaking molecules (GlycoSENS); tissue engineering
Extracellular aggregates	19078	Immunotherapeutic clearance (AmyloSENS)
Intracellular aggregates	19599	Novel lysosomal hydrolases (LysoSENS)

The "seven pillars of SENS anti-aging strategies" are shown in the table above, with a timeline of the discovery of their importance shown in the image below.

Important progress has recently been made on two of the pillars of SENS: Correcting for mutant mitochondria, and an improved clearing of cellular junk.

First, correcting human mitochondrial mutations:

Researchers at the UCLA stem cell center and the departments of chemistry and biochemistry and pathology and laboratory medicine have identified, for the first time, a generic way to correct mutations in human mitochondrial DNA by targeting corrective RNAs, a finding with implications for treating a host of mitochondrial diseases. Mutations in the human mitochondrial genome are implicated in neuromuscular diseases, metabolic defects and aging. There currently are no methods to successfully repair or compensate for these mutations, said study co-senior author Dr. Michael Teitell, a professor of pathology and laboratory medicine and a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Between 1,000 and 4,000 children per year in the United States are born with a mitochondrial disease and up to one in 4,000 children in the U.S. will develop a mitochondrial disease by the age of 10, according to Mito Action, a nonprofit organization supporting research into mitochondrial diseases. In adults, many diseases of aging have been associated with defects of mitochondrial function, including diabetes, Parkinson's disease, heart disease, stroke, Alzheimer's disease and cancer.

"I think this is a finding that could change the field," Teitell said. "We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans."

The study appears March 12, 2012 in the peer-reviewed journal Proceedings of the National Academy of Sciences. _esciencenews

More at the link.

Next, clearing cellular trash aggregates:

A University of Michigan cell biologist and his colleagues have identified a potential drug that speeds up trash removal from the cell's recycling center, the lysosome.

The finding suggests a new way to treat rare inherited metabolic disorders such as Niemann-Pick disease and mucolipidosis Type IV, as well as more common neurodegenerative diseases like Alzheimer's and Parkinson's, said Haoxing Xu, who led a U-M team that reported its findings March 13 in the online, multidisciplinary journal Nature Communications.

"The implications are far-reaching," said Xu, an assistant professor of molecular, cellular and developmental biology. "We have introduced a novel concept—a potential drug to increase clearance of cellular waste—that could have a big impact on medicine." _UMich News

More at the link.

Both of these developments will require a number of years to perfect and shape into useful therapies. But as noted, improved therapies in either domain would provide hope for slowing the ageing process, and for treating many of the degenerative scourges of human existence.

The SENS Foundation has worked to promote research in the seven areas pictured above. And at least partially due to the efforts of SENS, more researchers and funding agencies are picking up the same themes.

Cross-posted from Al Fin blog

Unconventional Brain Modifications

A team of neuroscientists had discovered a genetic manipulation which provides a long term increase in brain neurogenesis in mice, and which appears to boost learning and reduce anxiety and depression.

...genetic deletion of neurofibromin (Nf1), a tumor suppressor with RAS-GAP activity, in adult NPCs enhanced DG proliferation and increased generation of new neurons in mice. Nf1 loss-associated neurogenesis had the functional effect of enhancing behavioral responses to subchronic antidepressants and, over time, led to spontaneous antidepressive-like behaviors. Thus, our findings establish an important role for the Nf1-Ras pathway in regulating adult hippocampal neurogenesis, and demonstrate that activation of adult NPCs is sufficient to modulate depression- and anxiety-like behaviors. _Journal of Neuroscience

More from ScienceDaily news service:

The researchers found that the test group mice formed more neurons over time compared to controls, and that young mice lacking the Nf1 protein required much lower amounts of anti-depressants to counteract the effects of stress. Behavioral differences between the groups persisted at three months, six months and nine months. "Older mice lacking the protein responded as if they had been taking antidepressants all their lives," said Dr. Parada.

"In summary, this work suggests that activating neural precursor cells could directly improve depression- and anxiety-like behaviors, and it provides a proof-of-principle regarding the feasibility of regulating behavior via direct manipulation of adult neurogenesis," Dr. Parada said. _SD

This type of genetic manipulation will necessarily require further development before it is suitable for use in humans. In particular, it will have to be both reversible, and adjustable in effect.

The increase in hippocampal neurons also suggests the potential for augmenting learning ability in the altered mice over their full lifetimes.

Another interesting brain manipulation studied recently, is the use of the hallucinogenic drug LSD (lysergic acid diethylamide) to aid alcoholics in overcoming their addiction to ethanol. LSD has previously been used effectively to reduce cancer associated pain in terminal cancer patients, as well as to reduce or eliminate the fear of death in terminal cancer patients.

Here is more on a recent meta-analysis of the use of LSD for treating alcohol dependency:

Krebs and Johansen set out to independently extract data from previous randomized, controlled clinical trials, pooling their results. They identified six eligible trials, all carried out in the late 1960s and early 1970s. These included 536 participants, the vast majority of whom were male in-patients enrolled in alcohol-focused treatment programs. Individuals with a history of schizophrenia or psychosis were excluded from the original trials. The control conditions included low-dose LSD, stimulants, or non-drug control conditions. Each trial used clearly defined treatment-independent and standardized methods to assess outcomes on alcohol misuse.

While the experiments varied in the dosage used and the type of placebo physicians administered to patients, LSD had a beneficial effect on alcohol misuse in every trial. On average, 59 percent of LSD patients and 38 percent of control patients were improved at follow-up using standardized assessment of problem alcohol use. There was also a similar beneficial effect on maintained abstinence from alcohol. The positive effects of a single LSD dose -- reported both in these and in other, non-randomized trials -- lasts at least six months and appears to fade by 12 months. _ScienceDaily

Full study in Journal of Psychopharmacology (PDF)

Other hallucinogenic drugs besides LSD which may prove to have beneficial clinical uses include psilocybin, ketamine, and marijuana.

The human brain is an incredibly complex and dynamic organ. We should not be surprised when such a complex device sometimes "malfunctions." And we should maintain relatively open minds when in pursuit of ways to stabilise and improve brain function.

We are playing for very high stakes.

New Experimental Drug Offers Hope for Early Stroke Treatment

Number of deaths for leading causes of death
Heart disease: 599,413
Cancer: 567,628
Chronic lower respiratory diseases: 137,353
Stroke (cerebrovascular diseases): 128,842
Accidents (unintentional injuries): 118,021
Alzheimer's disease: 79,003
Diabetes: 68,705
Influenza and Pneumonia: 53,692
Nephritis, nephrotic syndrome, and nephrosis: 48,935
Intentional self-harm (suicide): 36,909 _CDC US Leading Causes of Death

As shown above, stroke -- cerebrovascular accident (CVA) -- is the 4th ranking cause of death in the US. Besides mortality, there is also significant morbidity and disability associated with stroke worldwide.

Recent research at Toronto Western Hospital provides reason to hope for better drug treatments for stroke in the near future. The researchers tested a new type of drug -- a PSD-95 inhibitor -- in primates, in an acute stroke setting. Some of their results are pictured below.

A phase 2 clinical trial in humans was also recently completed in Ontario.

Nature

In a series of experiments, Michael Tymianski and colleagues at Toronto Western Hospital in Ontario, Canada, replicated the effects of stroke in macaques before intravenously administering a PSD-95 inhibitor, or a placebo. PSD-95 inhibitors interfere with the process that triggers cell death when the brain is deprived of oxygen.

To test its effectiveness the team used MRI to measure the volume of damaged brain for 30 days following the treatment, and conducted behavioural tests at various intervals within this time.

Monkeys treated with the PSD-95 inhibitor one hour after stroke had 55 per cent less damaged tissue in the brain after 24 hours and 70 per cent less after 30 days, compared with those that took a placebo. These animals also did better in behavioural tests. Importantly, the drug was also effective three hours after stroke.

...An early stage clinical trial in humans, run by firm NoNO in Ontario has also seen positive results. _NewScientist

Nature study abstract

PSD-95 Overview

PSD-95 complex as drug target for antidepressant development

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure Interesting abstract providing information on underlying factors involved.

This is a line of treatment which has been obvious for decades, but which has lacked the proper basic science backing up until now. Although PSD-95 inhibitors will not prevent all brain damage from occurring in stroke, nor will they restore damaged brain to normal function afterward, they do seem to limit the amount of damage that occurs, for each stroke.

It is a type of stop-gap measure, meant to prolong relative normal function as long as possible. More optimal developments for the future will involve better preventive measures and ways to rejuvenate damaged brain after the insult occurs. Full spectrum medical care will eventually involve all avenues of treatment, prevention, and restoration.

Good News on the Alzheimer's Front

The number of Alzheimer’s victims worldwide is expected to double every 20 years... MIT neuroscientists have shown that an enzyme overproduced in the brains of Alzheimer’s patients creates a blockade that shuts off genes necessary to form new memories. Furthermore, by inhibiting that enzyme in mice, the researchers were able to reverse Alzheimer’s symptoms.

The finding suggests that drugs targeting the enzyme, known as HDAC2, could be a promising new approach to treating the disease, which affects 5.4 million Americans.

Histone deacetylases (HDACs) are a family of 11 enzymes that control gene regulation by modifying histones — proteins around which DNA is spooled, forming a structure called chromatin. When HDACs alter a histone through a process called deacetylation, chromatin becomes more tightly packaged, making genes in that region less likely to be expressed.

HDAC inhibitors can reverse this effect, opening up the DNA and allowing it to be transcribed.

In previous studies, Tsai had shown that HDAC2 is a key regulator of learning and memory. In the new study, her team discovered that inhibiting HDAC2 can reverse Alzheimer’s symptoms in mice._MIT

As the populations of the developed and emerging nations grow progressively older, the number of Alzheimer's sufferers -- and sufferers of other debilitating diseases of old age -- threaten to cripple these societies. Affordable means of preventing and treating dementias and other disabling diseases of senescence could make the difference between prosperity or poverty for many nations. The recent MIT discovery may be an important step forward in this regard.

... the team subsequently showed that using RNAi to reduce HDAC2 build up in the hippocampus of a mouse neurodegenerative disease model removed this repression, reinstated neuronal structural and synaptic plasticity, and eradicated neurodegeneration-associated memory deficits. Li-Huei Tsai, Ph.D., and colleagues report their findings in Nature in a paper titled “an epigenetic blockade of cognitive functions in the neurodegenerating brain.”

Epigenetic modifications in the nervous system that are mediated by histone acetylation have been unequivocally associated with facilitating learning and memory, the researchers state. Multiple studies have in addition reported that reduced histone acetylation is associated with cognitive decline in animal models of neurodegeneration including AD.

To further investigate the role of HDAC2 in neurodegeneration-related cognition, the team looked at levels of the enzyme in CK-p25 mice. These animals can be induced to overexpress p25, in the forebrain. p25 is a truncated version of p35 and is implicated in a range of neurodegenerative diseases. Their studies showed that animals induced to overexpress p25 demosntrated significant increases in HDAC2 in neuronal nuclei, specifically hippocampal area CA1 but not CA3 or the dentate gyrus, and also in the prefrontal cortex. In contrast, levels of the HDAC1 and HDAC3, were not changed.

The researchers then moved on to carry out chromatin immunopreciptation studies to assess the functional consequences of HDAC2 elevation, primarily in a range of known HDAC2 targets that have been shown to be downregulated in human AD brains, including learning- and memory-related genes, and those involved in synaptic plasticity. They found elevated HDAC2 enrichment at the majority of these genes induced CK-p25 hippocampus, whereas again, HDAC1 and HDAC3 binding wasn’t affected. “Interestingly, in agreement with previous reports showing that HDAC2 can also bind to a gene’s coding region, we also found HDAC2 more abundantly bound to the coding sequence of the same genes,” they note. _GenengNews

The researchers found that in mice with Alzheimer’s symptoms, HDAC2 (but not other HDACs) is overly abundant in the hippocampus, where new memories are formed. HDAC2 was most commonly found clinging to genes involved in synaptic plasticity — the brain’s ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories. In the affected mice, those genes also had much lower levels of acetylation and expression.

“It’s not just one or two genes, it’s a group of genes that work in concert to control different phases of memory formation,” Tsai says. “With such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions.”

The researchers then shut off HDAC2 in the hippocampi of mice with Alzheimer’s symptoms, using a molecule called short hairpin RNA, which can be designed to bind to messenger RNA — the molecule that carries genetic instructions from DNA to the rest of the cell.

With HDAC2 activity reduced, histone acetylation resumed, allowing genes required for synaptic plasticity and other learning and memory processes to be expressed. In treated mice, synaptic density was greatly increased and the mice regained normal cognitive function. _MIT

The MIT researchers have utilised a number of different advances in cell and molecular biology to make these discoveries. As scientists close in on the discovery of meaningful interventions in destructive pathological processes, the importance of pre-existing replicated "off the shelf" research grows.

This is good news for all mice who suffer from Alzheimer's. Now, scientists must confront the immense government-made mine field and obstacle course which obstructs modern efforts to affordably develop life saving interventions in the biomedical fields, for humans. In this sense -- as in many others -- government is the greatest enemy of the future.

Cross-posted from Al Fin