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  • sam patrick posted an article
    MUSC teams up for new clinical trial see more

    A combination of up to five drugs normally used to treat conditions ranging from HIV to Type 2 diabetes could destroy cancer cells yet be less toxic than a chemotherapy drug used for recurring ovarian cancer.

    After promising preclinical results, researchers at MUSC Hollings Cancer Center are now launching a phase 1 clinical trial to establish safe levels of various combinations of the drugs in patients with advanced solid tumors.

    Hollings researchers Joe Delaney, Ph.D., and Michael Lilly, M.D., are collaborating on the Combination of Autophagy Selective Therapeutics (COAST) trial, which already has enrolled its first patient.

    Autophagy is a cellular recycling process that occurs in all human cells, Delaney explained. Although the drugs in question – hydroxychloroquine, nelfinavir, metformin, dasatinib and sirolimus – were developed to treat, respectively, malaria, HIV, Type 2 diabetes and chronic myeloid leukemia and to prevent organ rejection in kidney transplant patients, what they all have in common is that they affect this cellular recycling process.

    “All the drugs on this trial affect autophagy in one way or another. Even though they were originally designed for these other diseases, we’ve learned from the decades of studying them that they actually impact this process of autophagy, which all human cells have,” Delaney said. “That’s true of our normal cells. And that’s also true of cancer cells. It’s just that the cancer cells cannot perform that recycling nearly as well as our normal cells can. And so, to us, that was our therapeutic window.”

     

      This slide illustrates Delaney's concept for utilizing the effect on autophagy by drugs already approved to treat other conditions.

    The National Cancer Institute encourages researchers to look into repurposing approved drugs, Lilly said. Already approved drugs have established safety records, whereas many potential new cancer drugs fail in early trials because they’re too toxic, Delaney said.

    Repurposed drugs, on the other hand, have already been used by potentially millions of patients. “It really puts you many years ahead in the developmental pathway,” Lilly said.

    In a paper published in June in Frontiers in Toxicology, Delaney showed that 14 doses of these five drugs were less toxic than Doxil, a chemotherapy drug used to treat ovarian cancer, multiple myeloma and AIDS-related Kaposi’s sarcoma. Now, the phase 1 trial will show safety levels in humans.

    “We’re really enthusiastic that this might be that opportunity to try multiple drugs,” Delaney said. “Since we started from that side effect profile to begin with, hopefully we have something that has much less toxicity. And of course, we’ll be finding out in the coming months if that’s actually true or not.”

    The drugs will be tested in a series of various combinations. Previous studies of drugs that target autophagy have mostly focused on adding one autophagy drug to a chemotherapy regimen or immunotherapy regimen, Lilly said. By combining multiple autophagy-targeting drugs, this trial hopes to identify a combination that prevents the cancer cells from evolving resistance to the drugs.

    “We have very good evidence that it’s a synthetic lethal combination for cancer cells, which is what everybody in cancer wants, but it’s just never been tried in people before. And so, we’re really excited to see this combination in a cancer setting,” Delaney said.

    Synthetic lethality refers to when mutations in two genes together result in cell death, but a mutation in only one of the partner genes does not.

    This human trial is a result of work in the lab that was funded by both the National Cancer Institute and donor Matt Prisby, who established a fund at Hollings for research into women’s cancers after his wife died of cervical cancer in 2014.

    “This trial couldn’t have happened without Matt Prisby and everyone who donated to his fundraisers,” Delaney said. “Dedicated funding programs like the one he established at Hollings are critical for investigators to get the early results that will convince large funding entities to invest in continued research along these lines.”

    Delaney also hopes that a combination of these drugs will prove effective for a broad swath of patients. Operating within the concept of precision oncology, researchers have been looking for ways to target mutations in patients whose tumors have been sequenced. Yet fewer than 10% of patients are eligible for precision therapy, Delaney said, referring to an area of medicine that uses information about a patient’s own genes to develop specific treatments that, in terms of cancer, target that individual’s tumor.

    This trial targets aneuploid gene changes – an extra or missing chromosome – which is common in cancer cells, ranging from 20% to 95% in advanced solid tumor patients.

    “If it works, many, many more patients could be eligible than for other targeted therapies,” Delaney said.

    The phase 1 trial is accepting patients with an advanced solid tumor of any type. Once the trial moves to phase 2, the researchers will focus on specific cancer types. Lilly said early indications are that these drugs might be particularly effective against ovarian and prostate cancers.

    Lilly, who treats patients with prostate cancer and runs his own lab focused on advanced prostate cancer, said that this collaboration with Delaney would only be possible at an academic cancer center like Hollings, where researchers work alongside the doctors who provide care to patients. Delaney and Lilly, each with their own areas of expertise, can share ideas, and patients have access to early trials like this.

    “Sherlock Holmes once referred to bits of data as having cumulative force when you have three or four different things, each of which points in the same direction,” Lilly said. “And that’s the power of collaborative research at Hollings.”

    The first video shows high-grade serous ovarian cancer cells grown in the lab and labelled with fluorescent proteins to measure how the molecular recycling process of autophagy is working in live cells.

    When the movie starts, the cells had just begun a treatment of a version of COAST therapy. As the movie progresses, the cells try to turn on autophagy in response to these COAST drugs - they fluoresce brighter.

    However, properly recycling autophagy would fluoresce red, whereas these cells fluoresce yellow, indicating their recycling system is jammed and cannot complete its function. As a result, these cancer cells accumulate too much cellular debris and pop, as seen by a sudden darkening of a single cell.

    The second video shows high-grade serous ovarian cancer cells grown in the lab and labelled with fluorescent proteins that label the nucleus of each cell in both green and blue.

    In the center top of the start of the movie, a cancer cell physically latches onto another cancer cell. Astonishingly, the cell is able to absorb the blue nucleus of this attached cell, thereby adding a whole extra genome to its own genome in the process. This is a live observation of one reason why cancer cells can evolve to resist chemotherapy: once they acquire that second genome, it is easier to shuffle genes around in a way that optimizes cancer cell growth.

  • sam patrick posted an article
    Improvements may one day improve the effectiveness and safety of chemotherapy see more

    For patients with cancer, the tumor-killing power of chemotherapeutic drugs is a double-edged sword. While many cancer drugs kill tumor cells, they can also harm healthy cells as they travel throughout the bloodstream.

    “A major limitation of chemotherapy agents is that only a tiny fraction goes to their targeted tumor,” said Dieter Haemmerich, Ph.D., D.Sc., professor at the Darby Children’s Research Institute within the Department of Pediatrics at the Medical University of South Carolina (MUSC). “As a result, there are side effects that include damage to the heart.”

    But what if you could “cleanse” the blood of chemotherapeutic drugs to reduce their harmful side effects? 

    In an article published in March 2022 in the journal Cancers, an MUSC research team led by Haemmerich reported that it had developed a device to remove excess chemotherapeutic drugs from circulation after cancer treatment. Using this device, the team removed 30% of the administered drug by one hour after treatment. Seed funding to develop the device was provided by a High Innovation - High Reward grant from the South Carolina Clinical & Translational Research Institute’s pilot project program.

    Haemmerich and his colleagues, including Katherine Twombley, M.D., a professor in the MUSC Department of Pediatrics, Division of Pediatric Nephrology, focused on doxorubicin (DOX), which is one of the most widely used chemotherapy drugs in adults and children. 

    DOX is also known to be toxic to the heart. This toxicity is particularly detrimental in pediatric patients, since any resulting heart failure will have negative health effects for the rest of the child’s life. In a 2006 clinical trial, DOX reduced cardiac function in children with leukemia, and steroid therapy was required to reduce its damaging effects.

    Despite its toxicity to the heart, DOX is a popular chemotherapy drug because it is highly effective at stopping cancer cells from dividing.

    “Doxorubicin works by basically damaging DNA,” said Yuri Peterson, Ph.D., an associate professor in the Department of Drug Discovery and Biomedical Sciences in the MUSC College of Pharmacy and an author of the article. “That is useful for treating cancer, but it can also cause off-target side effects like hair and bone marrow loss.” 

    Recent efforts to target DOX more precisely to the tumor site have included encapsulating it inside temperature-sensitive nanoparticles. These tiny particles are intact at normal body temperature and carry the drug through the bloodstream to the tumor. There, they can be heated with a probe to around 105 degrees Fahrenheit to release their DOX cargo.

    However, the technique has its own limitations. Only a fraction of the administered nanoparticles release their cargo when the heat is applied at the tumor site. Once the nanoparticles break down in the body, which can take as little as an hour, the remaining drug enters the bloodstream and can then cause side effects. 

    The MUSC research team wanted to improve outcomes with this technique by developing a device that would remove the leftover DOX after treatment.

    Using a rodent model of cancer, the researchers injected the heat-sensitive DOX nanoparticles and applied heat at the tumor site to release DOX. After treatment, they cleansed the blood of leftover DOX by first passing it through a heating element to get the nanoparticles to release the drug and then through an activated carbon filter to remove the drug from the blood before it was returned to the rodents’ circulation.

    Krishna Ramajayam, Ph.D., a postdoctoral fellow in Haemmerich’s laboratory in the Division of Pediatric Cardiology at MUSC, designed the heating element in the filtration device and supported the imaging studies for monitoring drug release and filtration.

    “Since the device is computer controlled, you can have very precise heating to ensure that the drug is released,” said Ramajayam. “The most exciting part for me is addressing both delivery and removal of the drug, which will improve patients’ quality of life immensely.”

    Importantly, the team also developed a method for detecting drug levels in the blood in real time to ensure that the drug is effectively removed.

    “By imaging the blood before and after filtration, we can actually predict how much drug is being removed in real time in the clinic,” said Anjan Motamarry, Ph.D., who completed work on the study while a doctoral student in Haemmerich’s lab before transitioning to a job in industry. “This would be very useful information for a clinician who needed to make a decision about when to stop filtration.

    ”Reducing the exposure of patients to leftover chemotherapy drugs could allow them to recover faster, with fewer side effects. It could also enable them to receive more chemotherapy cycles in the future in case additional treatment is necessary to kill the cancer cells.

    “Every drug has a maximum tolerated dose that you cannot go beyond,” said Motamarry. “Since we are removing the leftover drug after treatment, you can actually give an additional dose if the first cycle is not sufficient, which would not be possible if the drug was not removed.”

    Filtering the blood through the device also led to nearly three times less DOX in the heart, as measured using mass spectrometry at the MUSC Drug Discovery Core. Peterson and Thomas Benton, Ph.D., who was a doctoral student at MUSC at the time of the study, performed the measurements.

    These promising results suggest that the new device could reduce side effects in the heart that can be caused by chemotherapy, but more studies will be needed to confirm that promise.

    “If you deliver less drug to the heart, you will probably have fewer side effects,” said Haemmerich. “Our next step is to test the function of the heart directly after using this method in long-term animal tumor studies.”

    Further improvements to their device may one day improve the effectiveness and safety of chemotherapy in children and adults.

    “It’s really hard for anyone to go through chemotherapy,” said Motamarry. “This is the least that we can do to make it easier for them.”

  • sam patrick posted an article
    MUSC making its mark in cancer treatments see more

    Many cancer treatments such as chemotherapy and radiation kill cancer cells by inducing significant DNA damage beyond repair. But some tumors still develop alternative ways to survive. Now, scientists at the Medical University of South Carolina (MUSC) and Beth Israel Deaconess Medical Center have identified such a molecular pathway that helps cancer cells evade destruction.

    The protein ECT2 is critical for the activation of a backup survival mechanism cancer cells resort to as part of their response to DNA damage, the scientists described in a study published in the journal Science Signaling.

    As DNA damage response is essential for cell survival or death, better understanding of its mechanisms could lead to better combination therapies that can overcome tumor resistance, three researchers at the University of Illinois Chicago (UIC) said in an accompanying editorial.

    Scientists know that the kinase AKT is a key regulator of genome stability—hence cell survival—by mediating downstream signaling involved in DNA damage response and DNA repair. Increased activation of the enzyme has been linked to cancer progression and resistance to drugs. However, the exact mechanisms of AKT activation in the face of DNA damage were unclear.

    For its study, the MUSC and Beth Israel team treated multiple cancer cell lines with ionizing radiation or the chemotherapy etoposide and examined their responses. The researchers found that in response to drug-induced DNA damage, the DNA-PK enzyme modified a subunit of the mTORC2 protein complex.

    ECT2 recognized that interaction and subsequently promoted AKT activation, according to the team. When ECT2 was removed in cancer cells, treatment with etoposide didn’t induce AKT activation. Compared with control cells, these ECT2-depleted cells responded better to etoposide, showing decreased colony formation.

    What’s more, reintroducing ECT2 to the cells enhanced AKT activity, while an ECT2 mutant failed to do so, the team showed. Between the two groups, cells expressing normal ECT2 were less sensitive to etoposide partly because of reduced cell death.

    A cancer patient may go through multiple lines of treatment as cancer cells outsmart the drugs they encounter. Many research groups are exploring ways to render resilient tumors vulnerable to existing treatment. Last year, two teams of scientists demonstrated the promising effects of inhibiting an enzyme called POLQ on BRCA-mutated tumors that had stopped responding to traditional PARP inhibitors.

    A research team at the Swiss Federal Institute of Technology in Lausanne recently proposed adding CSF1R inhibition to control tumor-associated macrophages as a strategy to restore responses to the combination of PD-1/L1 immune checkpoint inhibitors, antiangiogenic drugs and chemo.   

    “Targeting the [DNA damage response] in cancer is of great clinical importance to traditional, current and emerging therapies including immunotherapy given the observed induction of antitumor immunity by DDR-targeted therapies,” the UIC researchers wrote in the editorial. 

    Findings from the current study pointed to combining DNA damage with DNA-PK-ECT2-mTORC2 network inhibition as a more efficient therapy against cancer, they said.