Carbon Chemist

Tag: Blood Cancer

  • Research identifies how leukemia develops resistance to first line treatments

    Research identifies how leukemia develops resistance to first line treatments

    [ad_1]

    Relapses in a common form of leukemia may be preventable following new research which has identified how the cancer develops resistance to first line treatments.

    New research published in iScience by researchers from the University of Birmingham, the Institute of Cancer Research (ICR), Newcastle University, the Princess Maxima Centre of Pediatric oncology and the University of Virginia identified changes in a mutated form of acute myeloid leukemia (AML) samples from patients who relapsed after receiving FLT3 inhibitor treatment.

    The team found that the resistant cancer had up-regulated multiple other signalling pathways to overcome the drug’s action, and that the genetic change was able to be replicated in lab tests.

    These experiments revealed that by targeting RAS family proteins, using a small molecule inhibitor developed from a chemical library screen using the paratope of an inhibitory intracellular antibody by Terry Rabbitts’ team at the Weatherall Institute of Molecular Medicine University of Oxford and the ICR, increased signalling no longer rescued the cells from cell death.

    The team identified that the transcription factors AP-1 and RUNX1 were at the heart of mediating drug resistance. The two factors cooperate and bind to their target genes together, but only in the presence of growth factor signalling. The drugs targeting FLT3 rewire the cell, resulting in the upregulation of other signalling pathway associated genes, which then restored AP-1 and RUNX1 binding. Drugging RAS, which is a key component in multiple signalling pathways, prevented this restoration of RUNX1 binding, and therefore signalling from growth factors no longer rescued the cancer cells from death.

    Professor Constanze Bonifer from the Institute of Cancer and Genomic Sciences at the University of Birmingham, who has just taken up a position at the University of Melbourne, and is one of the senior authors of the paper said:

    “The pharmaceutical industry had high hopes that drugs targeting aberrant growth factor receptors such as the FLT3-ITD would prevent people from relapse. However, cancer cells are smart, and rewire their growth control machinery to use other growth factors present in the body. Targeting RAS family members prevents the cancer from rewiring and using different signalling pathways to escape cell death.”

    Targeting RAS blocks rewiring

    The small molecule inhibitors used to target RAS in this study were developed using intracellular antibody technology. This technology involves screening a large number of antibody fragments to identify those which bind to the target protein in cells and prevent their protein-protein interactions. Small molecule inhibitors are can be screened from chemical libraries that interact with the parts of the target protein where these antibody fragments bind (the paratope). Due to the unparalleled natural specificity of these antibody fragments, this technology (called Antibody derived or Abd technology) can be used to target difficult to drug proteins and identify new parts of the protein which can be targeted to prevent protein-protein interactions.

    Professor Terry Rabbitts from the Institute of Cancer Research who developed these drugs said:

    “The strength of the Antibody-derived technology approach is that intracellular antibodies can selected to essentially any protein. In turn, their specific binding sites can be employed to select chemical compounds for drug discovery against hard to drug proteins. Mutant RAS was considered undruggable, but the Abd technology facilitated the development of the RAS-binding compounds used in the current study of cancer cell re-wiring. Abd technology will allow development of a new generation of drugs to hard-to-drug and intrinsically disordered proteins.“

    AML with a FLT3-ITD mutation occurs in nearly 30% of all patients and is a highly aggressive disease with a poor prognosis. This genetic change causes the expression of a mutant growth factor receptor which is always active and therefore cancer cells expressing it grow uncontrollably. While inhibitors which specifically target the FLT3 protein are now in use in the clinic, patients treated with these inhibitors frequently relapse.

    This work was funded by Leukaemia Research UK, the Medical Research Council, Blood Cancer Research UK, the Royal Society, the Wellcome and Cancer Research UK. The first author, Daniel Coleman is a John Goldman Fellow of Leukaemia UK.

    Source:

    Journal reference:

    Daniel J.L., et al. (2024). Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1. iScience. doi.org/10.1016/j.isci.2024.109576.

    [ad_2]

    Source link

  • Predicting treatment response in common blood cancer with DNA methylation profiling

    Predicting treatment response in common blood cancer with DNA methylation profiling

    [ad_1]

    A recent study led by Dr. Manel Esteller, Director of the Josep Carreras Institute, shows how DNA methylation profiling in a common type of blood cancer, myelodysplastic syndrome, predicts whether the patient will respond to treatment. This type of cancer can progress to acute myeloblastic leukemia, a much more serious disease. The outcomes could help in the early detection of patients who are resistant to demethylating drugs and in the design or administration of alternative treatments.

    There are many anti-cancer genes that are no longer active in human tumors, preventing them from carrying out their protective function against cell transformation. One of the main mechanisms used by cancer cells to silence these ‘good’ genes is the addition of a chemical modification called methylation, which results in the loss of gene expression. As this is a simple addition of a single “methyl” group, drugs have been designed to erase this signal and they have already been approved for use in cancer. These hypomethylating drugs are mainly used in malignant blood diseases such as leukemia. An article led by Dr Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute (IJC), ICREA Research Professor and Professor of Genetics at the Faculty of Medicine of the University of Barcelona, published in the British Journal of Haematology, shows how the DNA methylation profiling in common leukemia predicts whether the patient will respond to treatment. The groups of Dr Lurdes Zamora, Dr Blanca Xicoy and Dr Francesc Solé from the Josep Carreras Institute, as well as researchers from the Vall d’Hebron Hospital and the University of Bologna, have also collaborated in the study.

    “Our research has analyzed nearly 1 million genome methylation signals in patients affected by a type of blood cancer called myelodysplastic syndrome and who have been treated with the demethylating drug. We have found an epigenetic ‘fingerprint’ that is associated with a good clinical response to these drugs, which can help in the early detection of patients who are resistant to demethylating drugs and in the design or administration of alternative treatments“, comments Dr. Esteller on the article published in the official journal of the British Society of Haematology.

    Dr Esteller says they detected general patterns linked to the efficacy of the hypomethylating drug, but also single genes, which could facilitate the development of rapid and relatively inexpensive biomarkers to select responder patients and prepare rescue strategies for the rest. The researcher adds: “The genes we have found give us clues about the mechanisms involved in hypomethylating agents’ sensitivity. Some of them are tumor suppressor genes that now ‘wake up’ to inhibit tumor proliferation, as expected. In other cases, however, what the genes reactivation by the drug is likely to do is to produce proteins (antigens) and other molecules that alert our immune system to fight the disease. These data further support the use of cancer immunotherapy, which is likely to work even better in combination with the use of epigenetic drugs, such as the demethylating drugs included in our study”.

    Source:

    Josep Carreras Leukaemia Research Institute

    Journal reference:

    Noguera-Castells, A., et al. (2024) DNA methylation profiling of myelodysplastic syndromes and clinical response to azacitidine: A multicentre retrospective study. British Journal of Haematology. doi.org/10.1111/bjh.19392.

    [ad_2]

    Source link

  • Concomitant pharmacotherapy overcomes immunotherapy challenges in aggressive blood cancer

    Concomitant pharmacotherapy overcomes immunotherapy challenges in aggressive blood cancer

    [ad_1]

    Researchers at the University of Zurich and the University Hospital Zurich have discovered that a specific mutation in the cancer cells of an aggressive type of blood cancer can prevent novel immunotherapies such as CAR T-cell therapy from working. Their study also explains why the cancer cells are resistant and how this resistance can be overcome: through concomitant pharmacotherapy or genetically improved CAR T-cells.

    Acute myeloid leukemia (AML) is an aggressive form of blood cancer. It is caused by mutations in a large number of genes that are acquired in the course of a person’s life. One of these genes – the tumor suppressor gene TP53 – plays a key role. Normally, TP53 helps to prevent the development of tumors. Blood cancer patients in whom this gene is mutated, however, face an extremely poor prognosis, as their genes are resistant to conventional chemotherapeutic agents. Intensive research is therefore being carried out into new therapeutic approaches, such as CAR (chimeric antigen receptor) T-cells, which are already being used successfully for other cancers of the blood.

    Mutation in blood cancer cells weakens immunotherapy defense cells

    An international research team led by Professors Markus Manz and Steffen Boettcher from the University of Zurich (UZH) and the Department of Medical Oncology and Hematology at the University Hospital Zurich (USZ) has now shown that TP53-mutant AML cells are also significantly more resistant to a new type of immunotherapy – CAR T-cell therapy – than AML cells without the mutated gene.

    The reason for the poorer effect of CAR T-cells with mutated TP53 is that these immune cells are exhausted more quickly and are therefore less active against the cancer cells.”

    Steffen Boettcher, chief of service at USZ

    In CAR T-cell therapy, certain immune cells – the T-cells – are extracted from a patient’s blood. These immune cells are then genetically modified in the lab so that they form numerous new contact points (CARs) on their surface. Reintroduced into the patient, these CAR T-cells are able to recognize certain surface structures on the tumor cells, which enables the CAR T-cells to identify the cancer cells and destroy them in a targeted manner. Various CAR T-cell products are currently being tested against AML in early clinical trials.

    Concomitant pharmacotherapies or advanced CAR T-cells are effective against resistant cancer cells

    In their study, the researchers not only examined the mechanism underlying the resistance of mutated AML cells to CAR T-cell immunotherapy; they also found out how the endurance of CAR T-cells can be increased and a weak point of TP53-mutant AML cells can be exploited to overcome this resistance. Through additional pharmacological concomitant therapies or further genetic improvement of the CAR T-cells, they were able to drastically increase the effectiveness of CAR T-cells against TP53-mutant AML cells to the point where there was no longer any therapeutic difference compared to non-mutated AML cells.

    “This proof-of-principle study shows that concurrent pharmacological therapies and genetically engineered CAR T-cells are promising strategies to develop more effective and tolerable immunotherapies for patients with TP53-mutant AML,” says head of clinic Markus Manz.

    Source:

    Journal reference:

    Mueller, J., et al. (2024). Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells. EMBO Molecular Medicine. doi.org/10.1038/s44321-024-00024-2.

    [ad_2]

    Source link

  • City of Hope cures oldest person of blood cancer and achieves HIV remission

    City of Hope cures oldest person of blood cancer and achieves HIV remission

    [ad_1]

    City of Hope®, one of the largest cancer research and treatment organizations in the United States, treated the oldest person to be cured of a blood cancer and then achieve remission for HIV after receiving a blood stem cell transplant from a donor with a rare genetic mutation. Research published in NEJM today demonstrates that older adults with blood cancers who receive reduced intensity chemotherapy before a stem cell transplant with donor cells that are resistant to HIV may be cured of HIV infection.

    Paul Edmonds, 68, of Desert Springs, California, is the fifth person in the world to achieve remission for acute myelogenous leukemia and HIV after receiving stem cells with a rare genetic mutation, homozygous CCR5 Delta 32. That mutation makes people who have it resistant to acquiring HIV. Edmonds is also the person who had HIV the longest -; for over 31 years -; among these five patients.

    Known as the “City of Hope patient” among these five patients, Edmonds received a transplant at City of Hope on Feb. 6, 2019, and is now considered to be cured of leukemia. Edmonds stopped taking antiretroviral therapies for HIV nearly three years ago and will be considered cured of HIV after he has stopped taking antiretrovirals for five years. 

    “City of Hope’s case demonstrates that it is possible to achieve remission from HIV even at an older age and after living with HIV for many years,” said Jana K. Dickter, M.D., a clinical professor in City of Hope’s Division of Infectious Diseases, who led the study. “Furthermore, remission can be achieved with a lower-intensity regimen than the therapy received by the four other patients who went into remission for HIV and cancer. As people with HIV continue to live longer, there will be more opportunities for personalized treatments for their blood cancers.”

    For Edmonds’ medical team, this meant they would need to tailor his treatment to address his age and the duration of his HIV. City of Hope’s decades-long expertise treating older adults with cancer and HIV -; efforts led by John A. Zaia, M.D., director of City of Hope’s Center for Gene Therapy and Aaron D. Miller and Edith Miller Chair for Gene Therapy, and other doctors -; proved to be invaluable in treating Edmonds and helping him go into remission for both leukemia and HIV.

    Under the care of City of Hope hematologist Ahmed Aribi, M.D., assistant professor in the Division of Leukemia and a study author, Edmonds received three different therapies to get him into remission before receiving a transplant. The therapy is needed to help the patient achieve remission, and the patient can then proceed with a transplant with the goal of curing the cancer.

    Edmonds received a chemotherapy-based, reduced-intensity transplant regimen prior to his transplant that was developed by City of Hope and other transplant programs for treatment of older patients with blood cancers. Reduced-intensity chemotherapy makes the transplant more tolerable for older patients and reduces the potential for transplant-related complications from the procedure.

    For the transplant, Aribi and his team worked with City of Hope’s Unrelated Donor Bone Marrow Transplant Program -; directed by Monzr M. Al Malki, M.D. -; to find a donor who was a perfect match for the patient and had the rare genetic mutation, which is found in just 1-2% of the general population.

    The mutation makes people who have it resistant to acquiring HIV. CCR5 is a receptor on CD4+ immune cells, and HIV uses that receptor to enter and attack the immune system. But the CCR5 mutation blocks that pathway, which stops HIV from replicating.

    Edmonds had mild to moderate side effects caused by graft-versus-host disease, which occurs when the donor’s T lymphocytes, a type of white blood cell that fights infections, attack the patient’s cells.

    Edmonds also achieved “full chimerism,” meaning that all of his bone marrow and blood stem cells originated from the donor.

    Stephen J. Forman, M.D., director of City of Hope’s Hematologic Malignancies Research Institute and a professor in the Department of Hematology & Hematopoietic Cell Transplantation, noted a confluence of several research initiatives by City of Hope over the years helped lead the institution to this moment.

    City of Hope and other institutions started performing successful stem cell transplants in older adults a decade ago, an intensive and high-risk procedure in this population that was unheard of prior to then. We have treated patients who are in their 80s with transplants and that is due to City of Hope’s emphasis on expanding therapies to more patients, as well as our compassionate, top-notch care of even the most vulnerable populations.”

    Stephen J. Forman, M.D., Director of City of Hope’s Hematologic Malignancies Research Institute 

    “City of Hope is not stopping there. Our researchers are working on creating stem cells that have the genetic mutation that makes them naturally resistant to HIV, among other research initiatives,” he added. 

    These milestones include:

    • City of Hope was one of the first institutions in the United States to perform a reduced intensity regimen for older patients with myelodysplasia, a blood disease that can evolve into leukemia and that Edmonds had prior to acute myelogenous leukemia.
    • Ryotaro Nakamura, M.D., director of City of Hope’s Center for Stem Cell Transplantation and Jan & Mace Siegel Professor in Hematology & Hematopoietic Cell Transplantation, led the national trial that demonstrated a transplant could become standard of care for older people with myelodysplastic syndromes, which led to Medicare approving the therapy in older populations.
    • City of Hope was one of the first centers in the United States to perform effective, curative autologous transplants, which use a person’s own stem cells, for patients with HIV-related lymphoma. When many centers still treated patients with low-intensity, noncurative treatment approaches, City of Hope -; led by Forman and Amrita Krishnan, M.D., executive medical director of hematology, City of Hope Orange County – challenged that paradigm by demonstrating that autologous transplants could be used to cure patients with HIV-related lymphomas who would otherwise die.
    • City of Hope was also a primary national co-leader in two National Cancer Institute-sponsored trials for autologous as well as allogeneic stem cell transplantation, which use a donor’s stem cells, for patients with HIV and blood cancers. Led by Joseph Alvarnas, M.D., City of Hope’s vice president of government affairs and a hematology professor, these trials led to a change in the national standards of care on how best to manage this vulnerable patient population.

    City of Hope’s blood stem cell and bone marrow transplant (BMT) program has performed nearly 19,000 transplants, making it one of the largest programs in the nation. City of Hope has exceptional transplant outcomes year after year, according to the Center for International Blood & Marrow Transplant Research.

    Building on its BMT expertise, City of Hope is also a pioneer in the development of chimeric antigen receptor (CAR) T cells to treat blood cancers and solid tumors. More than 1,200 patients have been treated with CAR T cell therapy at City of Hope.

    Leveraging their expertise in cellular immunotherapy, City of Hope scientists have also developed chimeric antigen receptor CAR T cells that can target and kill HIV-infected cells and control HIV in preclinical research. A City of Hope clinical trial using CAR T cell therapy, which has the potential to provide HIV patients with a lifelong viral suppression without antiretroviral therapies, is expected to open later this year.

    Angelo Cardoso, M.D., Ph.D., City of Hope director of the Laboratory of Cellular Medicine, is also a study author and performed many of the experiments that confirmed Edmonds’ HIV remission.

    Source:

    Journal reference:

    Dickter, J. K., et al. (2024). HIV-1 Remission after Allogeneic Hematopoietic-Cell Transplantation. The New England Journal of Medicine. doi.org/10.1056/nejmc2312556.

    [ad_2]

    Source link