Chemist Han Xiao at Rice and biologist Xiang Zhang at Baylor and their labs have developed an antibody conjugate called BonTarg that delivers drugs to bone tumors and inhibits metastasis.

Their open-access study, which appears in Science Advances, shows how Xiao’s pClick technology can be used to link bone-targeting antibodies and therapeutic molecules.

In experiments, they used pClick to couple a molecule used to treat osteoporosis, alendronate, with the HER2-targeting antibody trastuzumab used to treat breast cancer and found it significantly enhanced the concentration of the antibody at tumor sites.

They reported the combination also inhibited secondary metastasis from infected organs seeded by bone tumors.

“Bone cancer is really challenging to treat, and clinical trials of different treatments have been disappointing for people with bone metastasis,” said Xiao, who joined Rice in 2017 with funding from the Cancer Prevention and Research Institute of Texas (CPRIT). “We feel our strategy is a real game changer.”

“Getting effective concentrations of drugs to bone tumors has been challenging because bones are hard, their networks of blood vessels is limited and drugs have tended to attach to adjacent healthy tissues,” Zhang said.

The new strategy employs bisphosphonates, a class of drugs typically used to treat osteoporosis. Bisphosphonates have a high binding affinity for hydroxyapatite, the main component of hard bone, and help overcome physical and biological barriers in the bone microenvironment.

They’re also amenable to binding with drugs through pClick, which uses a cross-linker to snap to specific sites on antibodies without having to re-engineer them with harmful chemicals, enzymes or ultraviolet light.

The result is a molecule that seeks out bone tumors and stays put, giving the drug time to kill tumor cells. It helps that bisphosphonate molecules prefer acidic sites like bone tumors, keeping the drug concentration higher there than in surrounding healthy tissue.

The researchers chose breast cancer drugs because while many recover from the disease, 20 to 40% of breast cancer survivors eventually suffer metastases to distant organs, with metastasis to bone occurring in about 70% of these cases, significantly increasing mortality, they said.

While chemotherapy, hormone and radiation therapy used to treat women with bone metastatic breast cancers can shrink or slow bone metastasis, they usually do not eliminate the metastases, Xiao said.

“Bone is kind of a fertile soil for cancer cell,” Xiao said. “If a cancer cell reaches it, then it has a really good chance to grow and to further migrate, for example to the brain, the heart, the liver or to other tissues. That’s a really bad situation for a patient.”

Xiao hopes to get the compound into a clinical trial, and sees potential for custom conjugates that treat other tumors prone to metastasis, including prostate cancer.

Postdoctoral researchers Zeru Tian of Rice and Ling Wu of Baylor are co-lead authors of the paper. Co-authors are graduate students Chenfei Yu, Yuda Chen, Axel Loredo and Kuan-Lin Wu and postdoctoral researcher Lushun Wang of Rice; and postdoctoral fellows Zhan Xu, Igor Bado and Weijie Zhang and instructor Hai Wang of Baylor.

Xiao is the Norman Hackerman-Welch Young Investigator, the Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and an assistant professor of chemistry, bioengineering and biosciences. Zhang is the William T. Butler, M.D., Endowed Chair for Distinguished Faculty, McNair Scholar, associate director of the Lester and Sue Smith Breast Center, professor of molecular and cellular biology and member of the Dan L Duncan Comprehensive Cancer Center.

The research was supported by CPRIT, the National Institutes of Health, the Robert A. Welch Foundation, the U.S. Department of Defense, the John S. Dunn Foundation, the Hamill Foundation, the Breast Cancer Research Foundation and the McNair Medical Institute.

Cancer is no different. Within a growing tumor, cancer cells with the best ability to compete for resources and withstand environmental stressors will come to dominate in frequency. It’s “survival of the fittest” on a microscopic scale.

But fitness — how well suited any particular individual is to its environment — isn’t set in stone; it can change when the environment changes. The cancer cells that might do best in an environment saturated with chemotherapy drugs are likely to be different than the ones that will thrive in an environment without those drugs. So, predicting how tumors will evolve over time, especially in response to treatment, is a major challenge for scientists.

A new study by researchers at Memorial Sloan Kettering in collaboration with researchers at the University of British Columbia/BC Cancer in Canada suggests that one day it may be possible to make those predictions. The study, published June 23, 2021, in the journal Nature, was led by MSK computational biologist Sohrab Shah and BC Cancer breast cancer researcher Samuel Aparicio. The scientists showed that a machine-learning approach, built using principles of population genetics that describe how populations change over time, could accurately predict how human breast cancer tumors will evolve.

“Population genetic models of evolution match up nicely to cancer, but for a number of practical reasons it’s been a challenge to apply these to the evolution of real human cancers,” says Dr. Shah, Chief of Computational Oncology at MSK. “In this study, we show it’s possible to overcome some of those barriers.”

Ultimately, the approach could provide a means to predict whether a patient’s tumor is likely to stop responding to a particular treatment and identify the cells that are likely to be responsible for a relapse. This could mean highly tailored treatments, delivered at the optimal time, to produce better outcomes for people with cancer.

A Trifecta of Innovations

Three separate innovations came together to make these findings possible. The first was using realistic cancer models called patient xenografts, which are human cancers that have been removed from patients and transplanted into mice. The scientists analyzed these tumor models repeatedly over extended timeframes of up to three years, exploring the effects of platinum-based chemotherapy treatment and treatment withdrawal.

“Historically, the field has focused on the evolutionary history of a cancer from a single snapshot,” Dr. Shah says. “That approach is inherently error prone. By taking many snapshots over time, we can obtain a much clearer picture.”

The second key innovation was applying single-cell sequencing technology to document the genetic makeup of thousands of individual cancer cells in the tumor at the same time. A previously developed platform allowed the team to perform these operations in an efficient and automated fashion.

The final component was a machine-learning tool, dubbed fitClone, developed in collaboration with UBC statistics professor Alexandre Bouchard-Côté, which applies the mathematics of population genetics to cancer cells in the tumor. These equations describe how a population will evolve given certain starting frequencies of individuals with different fitnesses within that population.

With these innovations in place, the scientists were able to create a model of how individual cells and their offspring, or clones, will behave. When the team conducted experiments to measure evolution, they found close agreement between these data and their model.

“The beauty of this model is it can be run forwards to predict which clones are likely to expand and which clones are likely to get outcompeted,” Dr. Shah says.

In other words, how the cancer will evolve is predictable.

A Foundation for the Future

The particular types of genetic changes the team looked at are called copy number changes. These are differences in the number of particular DNA segments in cancer cells. Up until now, the significance of these sorts of changes hasn’t been clear, and researchers have had doubts about their importance in cancer progression.

“Our results show that copy number changes have a measurable impact on fitness,” Dr. Shah says.

For example, the scientists found that, in their mouse models, treatment of tumors with platinum chemotherapy led to the eventual emergence of drug-resistant tumor cells — similar to what happens in patients undergoing treatment. These drug-resistant cells had distinct copy number variants.

The team wondered: What would happen to the tumor if they stopped treatment? Turns out the cells that took over the tumor in the presence of chemotherapy declined or disappeared when the chemotherapy was taken away; the drug-resistant cells were outmatched by the original drug-sensitive cells. This behavior indicates that drug resistance has an evolutionary cost. In other words, the traits that are good for resisting drugs aren’t necessarily the best for thriving in an environment without those drugs.

Ultimately, Dr. Shah says, the goal is to one day be able to use this approach on blood samples to identify the particular clones in a person’s tumor, predict how they are likely to evolve, and tailor medicines accordingly.

“This study is an important conceptual advance,” Dr. Shah says. “It demonstrates that the fitness trajectories of cancer cells are predictable and reproducible.”

The findings, published this week in Nature Communications, reinforce previous research which has found the parasite can prompt profound behavioral changes in its hosts, and potentially in the 2 billion people worldwide estimated to be infected by it. While T. gondii has been well studied in laboratory settings with humans and wild-caught rodents, this is one of the first studies to examine how the parasite effects wild host behavior during interactions with wild cats.

The research uses a rich data set from more than three decades of continuous field research in the Maasai Mara National Reserve in Kenya. It reveals that hyena cubs, but not subadult or adults, infected by T. gondii behave more boldly in the presence of lions, and that infected cubs have a greater risk of being killed by lions.

“This project is one of a handful of long-term continuous studies on a long-lived mammal,” said Zach Laubach, co-lead author on the study and postdoctoral fellow in ecology and evolutionary biology. “Our findings suggest that infection early in life leads to bolder behavior and is particularly costly for young hyenas.”

Many strains of T. gondii are found throughout the world, infecting warm blooded animals — including humans who have house cats — during different life stages through contaminated soil, drinking water or eating meat of other infected animals. It can also be passed down from mother to baby.

The researchers found that in the hyena populations they studied, infections are widespread but more common in older animals, meaning that it’s most likely that they become infected by consuming contaminated meat or water.

For infected cubs — hyenas up to one year old — they found infected animals are bolder, approaching lions from closer distances than uninfected cubs, and that infection among cubs also corresponds to a higher probability of being killed by lions. In this study, lions were the responsible for all hyena cub deaths among infected animals, but only 17% of uninfected cubs died before the age of one due to lion attacks.

This is a vulnerable time in the life cycle of spotted hyenas, who despite being proficient hunters, take a long time to develop and rely on support and protection from their mothers, according to Laubach.

“Hyena moms invest a ton of both time and resources into their offspring. They nurse until they’re about a year old and don’t reach independence until they’re about two or more years old,” said Laubach. “But after they’re one year old, we found no difference in how close they got to lions, regardless of infection status.”

Some scientists theorize that this parasite manipulates its hosts’ behavior (whether that host is a hyena or human) in order to get back to cats, where it can sexually reproduce. But the data from this study doesn’t provide enough evidence to disentangle the theory supporting an adaptive mechanism for the parasite from other plausible alternative theories. It does, however, show that T. gondii has a direct and detrimental impact on hyena fitness.

Measuring the cost of confidence

Maasai Mara National Reserve is a biological hot spot in southwestern Kenya, between Lake Victoria and the bustling city of Nairobi. For more than 30 years now, the Mara Hyena Project, led by co-author Kay Holekamp, has been gathering data on the health and behavior of spotted hyenas in one of the best places in the world to study a diverse array of large, carnivorous mammals.

“It’s really a one-of-a-kind system, especially for studying large carnivores in a natural setting, which is a rare opportunity,” said Laubach. “I can’t think of another place in the world where you can see the same numbers and diversity of species of large mammalian carnivores, it’s pretty spectacular.”

Laubach notes there are many misconceptions about hyenas. They’re quite social and live in large groups, some with more than 120 individuals. They’re also formidable in size and strength, at up to a 170 pounds when full grown (twice the size of a large dog) and they have one of the strongest jaws in the animal kingdom.

“They can eat bone, their bite can crack the femur of a giraffe,” said Laubach.

Yet hyenas and lions compete with one another for territory and food, and these interactions with lions are the leading natural cause of hyena injuries and mortality.

Because previous research has shown that T. gondii can impact behavior in animals in laboratory settings, what the researchers wanted to know was: How does T. gondii affect wild hyenas’ behaviors around lions, and what are the consequences?

Laubach and co-lead author Eben Gering analyzed archived data collect by numerous research assistants and graduate students. They gathered blood samples and documented the hyenas’ interactions with each other and when they interacted with lions. From the safety of their vehicle, researchers Benson (Malit) Pioon and Holekamp of the Mara Hyena Project administered tranquilizers to 166 hyenas, in order to draw and test their blood for the parasite. They found 108, or 65%, had been previously exposed.

Over the years, researchers spent many hours each morning and evening out in the field, recording hyena behaviors of individuals that can be identified by their unique spot patterns on their coats. The data revealed that infection with the parasite T. gondii was related to boldness and greater risk of lion mortality among hyena cubs but not older animals. The lack of an effect in older animals could be because they’ve had time to learn, while cubs have less than one year of experience to compete with the influence of the parasite.

“One limitation of this work is that it was an observational study. But limitations are interesting, because it points to what one might do next,” said Laubach. “We’d like to go back and tease apart how behaviors change in individuals by comparing how their behaviors differ before versus after infection.”

The study, published in the Journal of Investigative Dermatology, suggests that switching to a more balanced diet restores the gut’s health and suppresses skin inflammation.

“Earlier studies have shown that Western diet, characterized by its high sugar and fat content, can lead to significant skin inflammation and psoriasis flares,” said Sam T. Hwang, professor and chair of dermatology at UC Davis Health and senior author on the study. “Despite having powerful anti-inflammatory drugs for the skin condition, our study indicates that simple changes in diet may also have significant effects on psoriasis.”

What is psoriasis?

Psoriasis is a stubborn skin condition linked to the body’s immune system. When immune cells mistakenly attack healthy skin cells, they cause skin inflammation and the formation of scales and itchy red patches.

Up to 30% of patients with psoriasis also have psoriatic arthritis with symptoms such as morning stiffness and fatigue, swollen fingers and toes, pain in joints and changes to nails.

Diet affects the microbial balance in the intestines and skin inflammation

Food is one of the major modifiable factors regulating the gut microbiota, the community of microorganisms living in the intestines. Eating a Western diet can cause rapid change to the gut’s microbial community and its functions. This disruption in microbial balance — known as dysbiosis- contributes to gut inflammation.

Since bacteria in the gut may play key roles in shaping inflammation, the researchers wanted to test whether intestinal dysbiosis affects skin and joint inflammation. They used a mouse model to study the effect of diet on psoriasis and psoriatic arthritis. They injected mice with Interleukin-23 (IL-23) minicircle DNA to induce a response mimicking psoriasis-like skin and joint diseases.

IL-23 is a protein generated by the immune cells responsible for many inflammatory autoimmune reactions, including psoriasis and inflammatory bowel disease (IBD).

Hwang and his colleagues found that a short-term Western diet appears sufficient to cause microbial imbalance and to enhance susceptibility to IL-23-mediated psoriasis-like skin inflammation.

“There is a clear link between skin inflammation and changes in the gut microbiome due to food intake,” Hwang said. “The bacterial balance in the gut disrupted shortly after starting a Western diet, and worsened psoriatic skin and joint inflammation.”

One critical finding of their work was identifying the intestinal microbiota as a pathogenic link between diet and the displays of psoriatic inflammation. The study also found that antibiotics block the effects of the Western diet, reducing skin and joint inflammation.

Is the damage caused by an unhealthy diet reversible?

The researchers wanted to test if switching to a balanced diet can restore the gut microbiota, despite the presence of IL-23 inflammatory proteins. They fed mice a Western diet for six weeks before giving them an IL-23-inducing agent to trigger psoriasis and psoriatic arthritis features. Then, they randomly divided the mice into two groups: a group that continued the Western diet for another four weeks and a group that switched to a balanced diet for the same duration.

Their study showed that eating a diet high in sugar and fat for 10 weeks predisposed mice to skin and joint inflammation. Mice that were switched to a balanced diet had less scaling of the skin and reduced ear thickness than mice on a Western diet. The improvement in skin inflammation for mice taken off the Western diet indicates a short-term impact of the Western diet on skin inflammation.

This suggests that changes in diet could partially reverse the proinflammatory effects and alteration of gut microbiota caused by the Western diet.

“It was quite surprising that a simple diet modification of less sugar and fat may have significant effects on psoriasis,” said Zhenrui Shi, visiting assistant researcher in the UC Davis Department of Dermatology and lead author on the study. “These findings reveal that patients with psoriatic skin and joint disease should consider changing to a healthier dietary pattern.”

“This work reflects a successful collaboration among researchers, especially with Professor Satya Dandekar and her team at the Department of Medical Microbiology and Immunology and Professor Yu-Jui Yvonne Wan at the Department of Medical Pathology and Laboratory Medicine,” Hwang said.

The story of efforts to conserve the endangered oribi in South Africa represent a diaspora of issues as varied as the people who live there. On its surface, like many threatened species, you have conflict between a need for habitat and private landownership.

But dig a little deeper and you’ll uncover a seedy underbelly of political corruption, gambling, struggles over land, and racial tensions. No matter how much success is made through more traditional conservation efforts, says a new study by a University of Georgia researcher, the species will continue to be threatened until the human conflicts can be mitigated or resolved.

“It’s an interesting case study because the oribi is so dependent on habitat that’s on private lands,” said Elizabeth Pienaar, an associate professor at the University of Georgia Warnell School of Forestry and Natural Resources. “But it’s also a species that has gotten trapped in much larger political and social conflicts. … This is the dark side of conservation. We can say, look, the species needs X, Y and Z to survive and recover, but in cases like this, conservation efforts are mired in a complex political, social and historical framework. These much larger issues remain unresolved.”

For the oribi (OR-uh-bee), said Pienaar, solutions start with access to native grassland that has rapidly disappeared on the South African landscape. This means education for farmers who own land where oribi graze, but quickly scales up to include enforcement to prevent illegal poaching and even de-escalation of racial tensions during a time when land reform (the return of white-owned farmland to Black residents) is causing considerable conflict.

Meeting with farmers can help

Threatened or endangered species in other parts of the world face different issues, but the success of their conservation is likely tied up in socio-political webs, said Pienaar. The study, published recently in the journal Endangered Species Research, is the first of two parts that aim to provide insights for conservation agencies and organizations navigating similar waters. It was co-authored by master’s student Adrienne Louw and professor Adrian Shrader of the University of Pretoria.

Often, landowners want to conserve species because it’s part of their cultural heritage or because they care about wildlife and land stewardship. But a misunderstanding of the animals’ needs, a lack of outreach from government agencies due to budget constraints and a general mistrust of the government stemming from years of political conflict and corruption work against even the most basic education and outreach efforts.

“The farmers don’t want to be told what to do, but you can give them advice and they will implement it as they see fit,” added Pienaar. “That could be one of the most impactful things: somebody who is seen as a neutral third party going out there and just meeting with them. And the farmer will try a few things and if it doesn’t affect their profit margin, they’ll do it. That’s what they’re looking for — some advice.”

Separately, said Pienaar, local communities require employment and food security to reduce the need for illegal hunting. Poverty is a serious problem in South Africa, where 65.4% of the population lives below the poverty line, and infrastructure and service delivery in rural areas is poor. Improved economic and social security, including options to purchase meat at affordable prices, may reduce conflicts and poaching pressures. But poverty extends beyond financial insecurity, she added. Poverty is a lack of voice, an inability to define one’s future.

In addition, communities resent the loss of their traditional hunting rights under neocolonial management of wildlife. Poaching becomes a means of political protest against landowners and the government, particularly if the government is perceived to have failed communities by not providing needed services.

Underground gambling rings exacerbate the issue

These solutions only address a portion of the problem, though. Improving access to habitat and community services won’t stop a serious threat to oribi: illegal hunting at night, with trained greyhounds and hunting dogs, which sustains underground gambling rings.

Called “taxi hunting,” greyhound owners — who have the income or wealth to purchase these expensive hunting dogs — arrive at the edge of a farm under cover of night. The dogs, trained to run and capture the small antelopes, are fast and silent. Whoever’s dog catches the oribi wins the pot of money, as does the dog that kills the most antelope.

If a farm owner can’t stop the taxi hunt before the dogs are released, they are almost powerless to prevent it. It’s illegal for them to shoot a hunting dog that is with its handler, even if it’s on the farmer’s land. And if they do, there could be retribution in the form of arson, property damage or arrest of the farmer for shooting the dogs.

Then, add race into the mix: Farm owners are white, while the taxi hunters are black. “So, the farmers feel threatened because not only is there a push for land reform, but they are dealing with increased rural crime while also trying to prevent poaching by people who are not at risk of poverty,” said Pienaar. “It’s not just about protecting the oribi. It’s about protecting their family’s safety, their property and their heritage.”

And then there’s the oribi, stuck in the middle.

“But it’s not just the oribi. The oribi is a case study that is consistent with other species at risk, like rhinos and pangolins,” said Pienaar. “Biologists and ecologists are fantastic in terms of what these species need in terms of habitat or maintaining viable populations. But if you cannot resolve larger socio-political conflicts, the animal is still at risk. Most conservation issues, that I’m aware of, are about people and the pressures they face.”

What kinds of organisms thrive in this oceanic hotspot? In two new studies, MBL Assistant Scientist Emil Ruff and collaborators show that distinct regions within the Basin harbor specially adapted microorganisms; discover new microbial inhabitants of this deep-sea community; and suggest how the community may be dramatically influencing carbon cycling in the hot seafloor sediments.

Right at the seafloor where the geothermal heat meets the cold deep ocean, the sediments often have a cozy 30-60 °C, ideal temperatures for heat-loving microbes (thermophiles). These exotic heat-lovers can use methane as an energy source and thrive in seascapes that are so different from most other ecosystems on Earth that they could well exist on another planet entirely (see photo 1). The methane munchers and other organisms that use the chemical energy of the hydrothermal fluids are the base of the food web, without which the ecosystem would not be possible. In the first study, Teske et al. show that these methane munchers and other microbes are specially adapted to distinct thermal and geochemical regimes within the Basin.

The microbial communities in these hydrothermal sediments are very diverse, yet only a few organisms can use methane as an energy source. So, what is everyone else doing?

A large part — or most — of the microbial diversity seems to consist of organisms, which — like humans — can only use reduced organic compounds for energy (such as sugars, proteins and fatty acids). These organisms, called heterotrophs, must live in some way off the biomass that rains down from the surface ocean or is produced by the methane munchers and other primary producers.

It is a long-standing question what compounds these heterotrophs use to make a living and why so many different species can live side-by-side without outcompeting each other. In the second study, Sherlynette Pérez Castro, a postdoctoral scientist in Ruff’s lab at MBL, and collaborators show that certain heat lovers specialize in degrading the “debris” that is released to the environment when other cells perish: organic polymers and macromolecules.

Every cell, be it a microbial or a human cell, mainly consists of four types of macromolecules: protein, nucleic acids (DNA, RNA), lipids (fatty acids) and polysaccharides (sugars). The researchers used each one of these four compounds successively as the sole energy and carbon source to grow and identify those deep-sea organisms that can make a living on the respective compound.

They found that all of the organisms that they could cultivate in their lab experiments belonged to previously uncultivated microbial species. The experiments also showed that each polymer was nutrition for a whole food web of organisms, which explains how a single molecule can sustain a zoo of organisms, suggesting a reason for the high diversity of coexisting heterotrophs.

To their surprise, none of the 48 different cultures produced methane, a common end product of heterotrophic organisms. This could mean that the methane that is emitted at the seafloor is completely removed from the ecosystem by the microbial communities, which has implications for the deep-sea carbon cycle that remain to be explored.

Story Source:

Materials provided by Marine Biological Laboratory. Original written by Diana Kenney. Note: Content may be edited for style and length.