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Protein Switches: The Programmable Future of Bio-therapeutics
Curator: Dr. Sudipta Saha, Ph. D.
A PNAS paper entitled “A protein therapeutic modality founded on molecular regulation” presents a pioneering approach to creating protein switches—engineered enzymes that activate only in specific molecular environments. This design introduces a new class of context-dependent therapeutics for precision medicine.
Using domain-insertion techniques, researchers inserted ligand-binding domains into scaffold proteins like β-lactamase. These proteins remain inactive until encountering a specific small molecule, which triggers a conformational change and restores enzymatic activity. This offers precise spatiotemporal control—ideal for minimizing off-target effects.
One key innovation is the systematic insertional mutagenesis that identifies functional switch sites across the protein scaffold. This enables the construction of vast protein libraries, increasing the likelihood of finding optimal switch configurations. Furthermore, the approach is modular—different binding domains and enzymes can be combined to create switches tailored to specific clinical contexts.
These smart proteins can be programmed to respond to cancer biomarkers, metabolite levels, or disease-specific molecular cues. By activating only under disease conditions, they provide a blueprint for next-generation bio-therapeutics—potent, selective, and safer.
The method also opens avenues for drug delivery systems, diagnostics, and biosensors, where conditional activation is critical. Overall, this work represents a conceptual leap in synthetic biology and bioengineering, with implications spanning oncology, infectious disease, and regenerative medicine.
Sleeping Threats: Immune System’s Watch on Dormant Cancer
Curator: Dr. Sudipta Saha, Ph. D.
The immune system’s role in regulating dormant cancer cells has been increasingly elucidated, revealing a complex interplay that influences metastasis and cancer recurrence. Dormant cells, which enter a non-proliferative state, can evade immune detection and remain quiescent for prolonged periods.
Mechanisms of immune evasion include down-regulation of antigen presentation and residence within immune-privileged niches such as bone marrow. Both innate and adaptive immunity, particularly CD8+ T cells and natural killer cells, are involved in maintaining dormancy and preventing metastatic outgrowth.
Micro-environmental factors that modulate immune surveillance and dormancy status have been identified. Changes in cytokine profiles and inflammation can disrupt dormancy, leading to cancer cell reactivation and metastasis.
Therapeutic approaches to sustain dormancy or eliminate dormant cells are under development. These include immune checkpoint inhibitors, cancer vaccines, and cytokine modulators aimed at enhancing immune recognition and clearance.
By targeting dormant cancer cells through immune modulation, it is anticipated that metastasis can be delayed or prevented, significantly improving long-term patient outcomes and reducing cancer mortality.
Cancer Surgery Rethought: Immunotherapy Takes the Lead
Curator: Dr. Sudipta Saha, Ph.D.
In a recent phase 2 study published in The New England Journal of Medicine, the efficacy of nonoperative management was assessed in patients with mismatch repair–deficient (dMMR) solid tumors. Instead of undergoing curative-intent surgery, patients with stage I to III dMMR tumors were administered immune checkpoint inhibitors.
The study was conducted across two cohorts involving 117 patients. After two years of follow-up, a recurrence-free survival rate of 92% (95% CI, 86 to 99) was achieved. It was found that complete clinical responses could be maintained without surgical intervention, and substantial preservation of organ function was observed.
The avoidance of surgery was associated with fewer treatment-related complications and a significant improvement in patients’ quality of life. It has been emphasized that dMMR tumors, being highly immunogenic, respond exceptionally well to immune checkpoint blockade, thereby offering a viable alternative to conventional surgery-based treatment plans.
While the study’s findings have been considered ground breaking, long-term data have been recommended to fully validate this approach. Future studies are expected to refine patient selection criteria and monitoring strategies to ensure sustained outcomes.
Overall, a potential shift in the standard of care for patients with early-stage dMMR tumors has been proposed, highlighting how personalized immunotherapy can redefine oncological practice.
Shaping the Future: The Rise of Structural Nanomedicine
Curator: Dr. Sudipta Saha, Ph.D.
In their 2025 review, Mirkin, Mrksich, and Artzi describe how the field of structural nanomedicine is being transformed to revolutionize biomedical science. Therapeutic materials are now being designed with precise nanoscale architectures to optimize biological interactions, improve efficacy, and reduce side effects.
It is explained that, unlike traditional drug delivery methods, structural nanomedicine is centered on the engineering of form and function at the molecular level. Advances in DNA and RNA nanotechnology, self-assembling peptide systems, and engineered nanoparticles have been utilized to create customizable platforms capable of navigating complex biological environments. These structures are being programmed to respond to specific physiological triggers, thereby enabling targeted delivery and controlled release.
A strong emphasis is placed on how rational design principles—borrowed from materials science, chemistry, and bioengineering—are driving innovation. Examples are presented where precisely constructed nanostructures have been shown to outperform conventional therapies in cancer treatment, immunomodulation, and regenerative medicine.
Attention is drawn to the challenges that must still be addressed, including the scalability of manufacturing, regulatory barriers, and the need for deeper insights into nano-bio interactions at the systems level. It is argued that interdisciplinary collaboration will be required for the successful translation of structural nanomedicine from laboratory research to clinical application.
Ultimately, structural nanomedicine is portrayed as a paradigm shift—where passive carrier systems are being replaced by dynamic, functional architectures that actively engage in therapeutic processes. Optimism is expressed that through continued technological convergence, a new generation of precision therapies tailored to individual patients will be realized.
This review is recommended for researchers, clinicians, and industry professionals seeking to remain informed about future directions in biomedical innovation.
Resitu Medical Sets Stage for Breakthrough in Breast Tumour Removal
Curator: Dr. Sudipta Saha, Ph.D.
Resitu Medical, a Swedish company specializing in minimally invasive breast tumour removal, has announced the appointment of Stefan Sowa as its new Chief Executive Officer. Strategic leadership is being strengthened as the company moves towards commercialization in both European and American markets.
A novel electrosurgical device, designed to excise entire breast lesions during the biopsy procedure, is being developed by Resitu. The device is intended to minimize the need for open surgery by allowing intact removal of tissue with minimal bleeding, guided by real-time ultrasound imaging. Preclinical studies are currently being conducted, and preparations for FDA clearance and CE marking are underway.
ISO 13485 certification for the design, development, manufacturing, and sales of the device has been successfully obtained. Investment has been secured from major shareholders, including Novoaim, ALMI Invest Stockholm, and STOAF, to support the finalization of the product and the initiation of serial production for clinical trials.
Through the use of its technology, false negatives are hoped to be reduced, while patient outcomes and diagnostic accuracy are expected to be significantly improved. The burden on healthcare systems may also be alleviated by minimizing the need for recalls and secondary biopsies.
Positive attention has been garnered at major medical conferences, with workshops hosted at events such as the Uppsala Breast Meeting, and favourable media coverage has been achieved. With Stefan Sowa at the helm, Resitu’s innovative device is poised to transform breast cancer management practices globally.
Powerful Cancer-Fighting Foods and Their Role in Body Repair
Curator: Dr. Sudipta Saha, Ph.D.
In the search for dietary approaches to prevent and fight cancer, certain foods have been found to possess potent anti-cancer properties. These foods not only help reduce the risk of cancer but also assist in repairing the body. Five such foods are green tea, broccoli like vetables, papaya, purple potatoes, and pomegranate—and the bioactive compounds responsible for their benefits.
1. Green Tea
Green tea, particularly rich in the catechin epigallocatechin gallate (EGCG), has gained considerable attention for its cancer-fighting properties. EGCG functions as a potent antioxidant, neutralizing free radicals and reducing oxidative stress, which is a key factor in the development of cancer. Studies suggest that EGCG can inhibit cancer cell proliferation by disrupting the signaling pathways essential for cell growth and survival, especially in breast, prostate, and colorectal cancers. Additionally, green tea has been shown to enhance the body’s immune function, making it more effective at targeting abnormal cells. EGCG induces apoptosis (programmed cell death) in cancer cells, halts angiogenesis (the formation of new blood vessels that nourish tumors), and inhibits metastasis (the spread of cancer cells to other parts of the body).
2. Broccoli and Cauliflower
Cruciferous vegetables like broccoli and cauliflower are rich in sulforaphane, a compound known for its detoxifying and anti-carcinogenic properties. Sulforaphane activates the body’s natural detoxification enzymes, which help eliminate carcinogens before they can damage cells. Moreover, it has been shown to inhibit the growth of various cancer cells, including those of the colon, breast, and prostate. Sulforaphane enhances the activity of phase II detoxification enzymes and induces apoptosis in cancer cells. It also inhibits histone deacetylase, an enzyme associated with cancer cell growth, thus preventing cancerous cells from replicating.
3. Papaya
Papaya is rich in carotenoids such as beta-carotene, lycopene, and beta-cryptoxanthin, which are powerful antioxidants. These compounds neutralize free radicals, reducing oxidative stress that can lead to cancer. Lycopene, in particular, has been linked to a lower risk of cancers, including those of the prostate, breast, and lung. Papaya also contains other bioactive compounds that help modulate immune responses, supporting the body’s ability to identify and destroy cancer cells. Carotenoids act by scavenging free radicals and reducing oxidative stress. Lycopene has also been shown to regulate cell cycle progression and inhibit growth factor signaling in cancer cells.
4. Purple Potatoes
Purple potatoes are unique due to their high levels of anthocyanins, which not only provide them with their distinctive color but also contribute to cancer prevention. Studies suggest that anthocyanins in purple potatoes help repair damaged tissues by promoting stem cell regeneration. They also have anti-inflammatory and anti-proliferative effects, which are crucial for halting cancer growth. Anthocyanins inhibit the growth of cancer cells by inducing cell cycle arrest and promoting the repair of damaged tissues through stem cell activation.
5. Pomegranate
Pomegranates are rich in ellagitannins, compounds that break down into ellagic acid in the body. Ellagic acid has been shown to possess anti-cancer properties by inhibiting tumor growth and promoting apoptosis in cancer cells. Pomegranate juice has demonstrated potential in reducing the progression of cancers such as breast and prostate cancer, due to its ability to suppress inflammation and oxidative stress. Ellagitannins and their metabolites inhibit cell proliferation and induce apoptosis. They also act by reducing inflammation and inhibiting the pathways involved in cancer cell survival and growth.
Conclusion
Incorporating foods like green tea, broccoli, papaya, purple potatoes, and pomegranates into your diet may help fight cancer and promote the repair of damaged tissues. The bioactive compounds found in these foods—EGCG, sulforaphane, carotenoids, anthocyanins, and ellagitannins—work through various mechanisms to inhibit cancer cell growth, induce apoptosis, and support the body’s natural repair processes. Including these nutrient-dense foods in your diet may contribute to overall health and resilience against cancer.
A large clinical trial has shown that pembrolizumab (Keytruda), an immunotherapy drug, nearly doubles the cancer-free survival time for patients with high-risk, muscle-invasive bladder cancer following surgery. The study, published on September 15, 2024, in The New England Journal of Medicine, was led by NIH researchers and demonstrated that pembrolizumab outperforms traditional observation methods post-surgery. Patients receiving pembrolizumab had a median cancer-free survival of 29.6 months, compared to 14.2 months for the observation group.
The trial enrolled 702 participants, some of whom had previously undergone cisplatin-based chemotherapy (neoadjuvant therapy). Pembrolizumab was administered every three weeks for a year. The drug was well tolerated, with common side effects including fatigue, itching, diarrhea, and thyroid issues.
Interestingly, the benefit of pembrolizumab was seen regardless of the tumor’s PD-L1 status.
Patients with PD-L1-positive tumors had a median cancer-free survival of 36.9 months.
Patients with PD-L1-negative tumors experienced 17.3 months cancer-free.
These results suggest that PD-L1 status should not be the sole factor in selecting patients for this therapy.
While overall survival rates were similar between the pembrolizumab and observation groups, many patients in the observation group began taking nivolumab once it was approved, complicating survival comparisons. Researchers are continuing to explore other treatment combinations and biomarkers to better personalize adjuvant therapy for bladder cancer patients.
Armored CD7-CAR T Cells: A Fratricide-Resistant Solution for T-ALL Therapy
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
This research reported in Nature Medicine addresses the challenge of treating T-cell acute lymphoblastic leukemia (T-ALL) with CAR T-cell therapy, particularly focusing on CD7, a surface marker highly expressed on T-ALL cells. The authors develop a novel CAR T-cell therapy that targets CD7, but with a crucial innovation which is fratricide resistance.
Fratricide, a phenomenon where CAR T cells kill each other (killing sister cells) due to shared CD7 expression, has been a significant problem in using CD7-directed therapies. To overcome this, the researchers made CD7-negative CAR T cells (CD7-CAR T cells) by knocking out CD7 from the CAR T cells themselves, preventing them from attacking one another.
Their preclinical results show that these CD7-CAR T cells exhibit strong anti-leukemic activity in T-ALL models, both in vitro and in vivo.
The fratricide-resistant T cells not only maintain their potency but also display enhanced proliferation and persistence, crucial for sustained therapeutic effects. Additionally,
the study highlights the feasibility and safety of this approach by demonstrating no adverse off-target effects or side effects, making it a potentially promising treatment for T-ALL patients who have limited options.
The research presents a significant advancement in CAR T-cell therapy by addressing the challenge of fratricide, offering a new, effective, and safe therapeutic option for T-ALL patients. The development of fratricide-resistant CD7-CAR T cells could lead to more successful outcomes in clinical applications, revolutionizing the treatment for T-ALL patients.
Live Conference Coverage: International Dialogue in Gynecological Oncology, From Bench to Bedside, Ovarian Cancer
Reporter: Stephen J. Williams, Ph.D.
Join Live on Wednesday May 22, 2024 for an international discussion on the current state of ovarian cancer diagnostics and therapeutics, and potential therapies and biomarkers, and biotargets. Topics including potential new molecular targets for development of ovarian therapeutics, current changes in ovarian cancer clinical treatment protocols, chemo-resistance, and the use of Artificial Intelligence (AI) in the diagnosis and treatment of cancer will be discussed.
10/15.10 We Have Never Been Only Human: a new perspective to defeat ovarian cancer (C. Martinelli)
Molecular Section
20/15.20 DNA Repair mechanisms: understanding their role in cancer development and chemoresistance (L. Alfano)
35/15.35 Progranulins: a new target for oncological treatment (A. Morrione)
50/15.50 Modulation of gene expression and its applications (M. Cuomo)
10.05/16.05 Commanding the cell cycle: the role of CDKs (S.R. Burk
10.20/16.20 Drug development from nature (M. D’Angelo
Clinical Section
05/17.05 Core principles of Radiologic Diagnosis & Staging in Ovarian Cancer(A. Blandino)
20/17.20 Key Indications for Nuclear Medicine in Ovarian Cancer (S. Baldari)
35/17.35 Cutting Edge Decision: Understanding Surgical Indications and Outcomes in Ovarian Cancer (A. Ercoli)
50/17.50 Gold Standard in Oncology for Ovarian Cancer (N. Silvestris)
12.05/18.05 Role of Radiotherapy in Ovarian Cancer (S. Pergolizzi)
Conclusion
12.20/18.20 AI Applied to medical science (V. Carnevale)
Speakers
– Professor Alfredo Blandino: Professor Blandino holds the esteemed positions of Head of school of Radiology and director of the department of radiology at the University of Messina. He has made significant contributions to diagnostic imaging with over hundreds of publications to his name, Professor Blandino’s work exemplifies excellence and innovation in radiology.
– Professor Alfredo Ercoli, serves as the Director of the Department of Gynecology and Obstetrics at the “G. Martino” University Hospital in Messina. He is also head of school of gynecology and obstetrics at Messina University. Starting his research in France with studies on pelvic anatomy that became a cornerstone in medical literature, He is a pioneer in advanced gynecologic surgery, including laparoscopic and robotic procedures, having performed over thousands of surgical interventions. His research focuses on gynecologic oncology, advanced gynecologic surgery, and endometriosis, urogynecology. Professor Ercoli’s dedication to education and his numerous publications have significantly advanced the field of gynecology.
–Professor Sergio Baldari, an eminent figure in nuclear medicine. Professor Baldari is the Director of the department of nuclear medicine and head of school of nuclear medicine at the University of Messina. He has authored or co-authored over 500 publications, with a focus on diagnostic imaging and the use of PET and radiopharmaceuticals in cancer treatment. His leadership and expertise have been recognized through various prestigious positions and awards within the medical community.
– Professor Nicola Silvestris is the Director of UOC Oncologia Medica at the University of Messina. His extensive research in cancer, has led to over 360 peer-reviewed publications. Professor Silvestris has made significant contributions to translational research and the development of guidelines for managing complex oncological conditions. His work continues to shape the future of cancer treatment.
–Professor Stefano Pergolizzi, a leading expert in radiation oncology. Professor Pergolizzi serves as the Director of the department of radiotherapy and head of the school of radiotherapya at the University of Messina. He is also the president of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) His research focuses on advanced radiotherapy techniques for cancer treatment. With a career spanning several decades, Professor Pergolizzi has published numerous papers and has been instrumental in developing innovative therapeutic approaches. His dedication to patient care and education is exemplary.
Margherita D’angelo: Graduated in Molecular Biology with honors from the Federico II University of Naples.
Third year intern in Food Science at the Luigi Vanvitelli University of Naples.
Research intern in Molecular oncology with the project of developing novel drugs starting from food waste at the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University, Philadelphia (USA), directed by Dr A. Giordano.
Dr. Carnevale is an Associate Professor in the Institute for Computational Molecular Science in the College of Science & Technology, Temple University. He holds multiple NIH RO1 and NSF grants. Vincenzo Carnevale received B.Sc. and M.Sc. degrees in Physics from the University of Pisa and a PhD from SISSA – Scuola Internazionale Superiore di Studi Avanzati in Trieste, Italy. The Carnevale research group uses statistical physics and machine learning approaches to investigate sequence-structure-function relations in proteins. A central theme of the group’s research is how interactions give rise to collective phenomena and complex emergent behaviors. At the level of genes, the group is interested in epistasis – the complex entanglement phenomenon that causes amino acids to evolve in a concerted fashion – and how this shapes molecular evolution. At the cellular level, the group investigates how intermolecular interactions drive biomolecules toward self-organization and pattern formation. A long-term goal of the group is understanding the molecular underpinnings of electrical signaling in excitable cells. Toward these goals, the group applies and actively develops an extensive arsenal of theoretical and computational approaches including statistical (mean)field theories, Monte Carlo and molecular dynamics simulations, statistical inference of generative models, and deep learning.
Professor Andrea Morrione, Ph.D: Research Associate Professor, CST Temple University; After his studies in Biochemistry at Universita’ degli Studi Milano, Milan Italy, Dr. Morrione moved to USA in 1993 and has been working in the field of cancer biology since his postdoctoral training at the Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA in the laboratory of Dr. Renato Baserga, one of the leading experts in IGF-IR oncogenic signaling. In 1997 Dr. Morrione joined the Faculty of Thomas Jefferson University in the Department of Microbiology. In 2002 after receiving an NIH/NIDDK Career Development Award Dr. Morrione joined the Department of Urology at Jefferson where from 2008 to 2018 serves as the Director for Urology Basic Science and Associate Professor. Dr. Morrione joined the Department of Biology and the Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology as Associate Professor of Research, and he is currently professor of Research and Deputy Director of the Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology. He is a full member of the AACR.
Canio Martinelli, M.D.: Dr. Marinelli received his MD from Catholic University of the Sacred Heart in Rome, Visiting researcher at SHRO Temple University in Philadelphia, PhD candidate in Translational Molecular Medicine and Surgery & GYN-OB resident at UNIME. He has published numerous clinical papers in gynecologic oncology, risk reduction, and therapy and, most recently investigating clinical utilities of generative AI in gynecologic oncology.
Sharon Burk, Sharon Burk is a PhD student with Professor Antonio Giordano at the University of Siena, Italy in the department of Medical Biotechnologies, studying the role of Cyclin Dependent Kinase 10 in Triple Negative Breast Cancer. She received her Bachelor’s of Arts Degree from the University of California, Berkeley with a double major in molecular and cell biology and Italian studies. She is a member of AACR.
AACR 2023 Meeting Highlights: Reports from Plenary Sessions and Major Symposium Talks
Reporter: Stephen J. Williams, Ph.D.
Highlights from Sunday April 16,2023
Nobel Laureate will discuss her work investigating the glycobiology of cancer
Carolyn R. Bertozzi, PhD, shared the Nobel Prize in Chemistry in 2022 for her invention of bioorthogonal chemistry, which is a class of chemical reactions that are compatible with living systems. These chemistries allow researchers to explore molecular imaging and drug targeting without interfering with natural biological processes. Bertozzi’s AACR Award for Outstanding Achievement in Chemistry in Cancer Research, and her lecture, focus on the glycobiology of cancer.
Carolyn R. Bertozzi, PhD
“There is a family of receptors on immune cells that bind carbohydrates,” said Bertozzi, Baker Family Director of the Sarafan ChEM-H Institute and Anne T. and Robert M. Bass Professor of Chemistry at Stanford University. “Called the ‘sialic acid-binding immunoglobulin-like lectins’ — abbreviated Siglecs — these receptors bind carbohydrates that possess the sugar sialic acid. There are 14 Siglec family members in humans and they are found in various combinations on every type of immune cell — T cells, macrophages, neutrophils, NK cells, all of the immune cell types that are important in anti-cancer immunity. As tumors progress, they often overexpress sialoglycan ligands for Siglecs, which allows them to engage these receptors and suppress immune-cell reactivity. We have focused on developing immune therapies that disrupt Siglec-ligand interactions.”
Bertozzi will discuss this area of her research during her award lecture, Targeting the Glycocalyx for Cancer Immune Therapy, at 4:30 p.m. ET Sunday in Tangerine Ballroom 3-4 (WF3-4) at the convention center.
“The signaling biochemistry of the Siglec family of checkpoint receptors is similar to the signaling biochemistry that PD-1 participates in,” Bertozzi explained. “They are like PD-1 except that they bind sugars rather than proteins, and they are present on every type of immune cell, including activated T cells, but also myeloid-derived cell types.”
“Glycobiology is an important area to become more familiar with if you want to truly be able to move the needle,” she said. “The science we have uncovered has led to the identification of exciting new targets, which has enabled us to invent new therapeutic modalities.”
Familiar small molecules and antibodies are of marginal use in targeting sugars, Bertozzi explained. Because carbohydrates are different types of molecules than traditional cancer targets, they need nontraditional mechanisms of action.A new class of targeted enzymes can edit the cell surface glycocalyx (or sugar coating) and deprive cancers of their ability to engage Siglec receptors. Without the broad inhibitory activity of Siglecs, the immune system remains free to engage and, hopefully, destroy tumors. At least one investigative agent is in phase I human trials and is poised to move into phase II.
“Glycobiology might explain why so many patients don’t respond to anti-PD-1 and anti-PD-L1 antibodies,” Bertozzi said. “We think a large fraction of tumors suppress the immune response through Siglec engagement.”
Other Articles on Real Time Coverage of AACR Meetings on this Open Access Scientific Journal Include:
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