Breast cancer treatment options have significantly expanded in the past decade, welcoming new classes of agents as well as treatments directed at specific patient populations (TIMELINE).

Many believe that these advancements in breast cancer care over the past 10 years owe much to the increased understanding of molecular factors contributing to breast cancer pathogenesis and heterogeneity.1-3

In looking back at the past decade of targeted therapy in breast cancer, Targeted Therapies in Oncology (TTO) spoke with 2 medical oncologists with extensive expertise in breast cancer about how biomarker advancements have transformed the practice of breast cancer management.

I think its fair to say that breast cancer in particular has led the way in molecular therapeutics in oncology, Dennis J. Slamon, MD, director of clinical/translational research at the UCLA Jonsson Comprehensive Cancer Center, told TTO. In part, thats because of all the investment that was made in research [and] because of defi ning this disease not just at a tissue level, but at a molecular level.

Classification of breast cancers into not just hormone receptor and HER2 positivity or negativity, but also into the luminal/basal subtypes has helped to identify treatments that may be more helpful for large groups of patients.1,3 For example, patients with basal-like disease, which is about 15% to 20% of all breast cancers, have triple-negative breast cancer (TNBC) and a poor prognosis. These patients tend to be responsive to chemotherapy treatment.1

The fact that molecular targets did not consistently translate to all breast cancers has become a key underpinning of our understanding of cancer.1 Not all patients benefi t from molecularly targeted treatments. For instance, HER2-positive breast cancer only accounts for about 25% of all breast cancer cases, thus HER2-targeted therapies may only benefi t 25% of all patients with breast cancer.

The same story is coming up again and again, not necessarily the same genes or the same targets or the same pathways, but the fact that there is a diversity of these diseases thats far beyond what we used to use to classify cancers by the tissue in which they arose, Slamon said.

Our understanding of cancer as a potentially more complex disease than previously supposed, began to develop well before 2012, explained Slamon.

That started in breast cancerbefore molecular medicine, as far back as 1899 or 98, when a surgeon recognized the fact that this disease occurred in women and the fact that it may have some hormonal component, said Slamon.4 After we found HER2, the methods of dissecting a tumor molecularly became much more sophisticated and widespread in their use and now, today, there are 14 molecular subtypes of breast cancer. And that is the underpinning of how breast cancer has led the way [in determining that patients with breast cancer] should not be treated with a one-size-fits-all approach. They should be treated with therapeutics that are directed to the appropriate subtype or the class in which they sit.

These molecular subtype characterizations have also shaped the therapeutic strategies within different breast cancer settings. Just thinking about advances in targeted therapies and how we use them to treat breast cancer in the last decade, I separate it into 2 categories1 is how we treat localized breast cancer,when our goal is to cure the cancer, so stages I to III. Most patients are being diagnosed with those earlier stages of breast cancer, Marina Sharifi , MD, PhD, assistant professor and medical oncologist at the University of Wisconsin Carbone Cancer Center, told TTO.

I think one of the major themes over the last 10 years for these nonmetastatic breast cancers is what I refer to as right-sizing therapy. We know that some of the women who have these early breast cancers can have recurrence down the road and we want to try and prevent that. So, 10 to 15 years ago, all of those women got chemotherapy, but even back then we knew that not every woman needs chemotherapy, and we knew that there were some breast cancers that could potentially benefit from more targeted types of therapies. But in the past 10 years, there have been a few developments that have allowed us to determine which women need chemotherapy and which women we can safely avoid exposing to the [adverse] effects of chemotherapy, said Sharifi.

This new prognostic ability has been fueled by advances in genomic testing.5,6 In addition to hormone receptors and molecular subtypes, other prognostic biomarkers that have been incorporated into practice include transcriptomic and proteomic levels and Ki-67 levels. Other biomarkers utilize combinations of genes to determine potential responses to treatment as well as the possibility of recurrence.

And more recently, research has turned to the use of circulating DNA and circulating tumor cells to help identify further prognostic and predictive bbiomarkers for patients with breast cancer.6

Specifically, for estrogen-driven (estrogen receptor [ER] positive) breast cancers, which are the most common type of breast cancer, we have genomic tests that are now used routinely to help us identify women who can safely avoid chemotherapy with that type of breast cancer. Both the MammaPrint and the OncoType DX are genomic tests that we know are effective in identifying which women do need chemotherapy to help maximize their chances of cure and which women have lower-risk breast cancers where the chemotherapy actually wont help them because they dont need it.7,8 That has been a huge development in the fi eld in the last 10 yearsto go from knowing that these tests were out there but not having that confirmation that we know that they predict chemotherapy benefit to having 2 major trials come out in the last 10 years that demonstrate that they can predict chemotherapy benefit, both in women who have those ER-positive breast cancers without lymph node involvement and also women who have ER-positive breast cancer with lymph node involvement. That has been a major advance for the most common type of breast cancer thats diagnosed across the country.9,10

Both the TAILORx (NCT00310180) and RxPONDER (NCT01272037) trials validated the usefulness of the 21-gene Oncotype DX recurrence score assay in patients with hormone receptorpositive, HER2-negative breast cancer. The TAILORx trial showed that among patients with node-negative disease, those with an intermediate Oncotype DX score, or intermediate risk of recurrence, could benefit from treatment with endocrine therapy alone and avoid receiving chemotherapy. Younger patients (.50 years) with a recurrence score of 16 to 25 still showed some benefit from the combination of chemotherapy and endocrine therapy.9 I n R xPONDER, adjuvant chemotherapy use was not considered necessary in most postmenopausal women with node-positive disease and recurrence scores between 0 and 25. Alternatively, premenopausal women were more likely to benefit from adjuvant chemotherapy.10

On the fl ip side, said Sharifi , somehave high-risk TNBC or high-risk HER2-positive breast cancer, those are types of breast cancer where historically we have struggled to cure women. There weve had a number of different advances. In TNBC, weve had the introduction of immunotherapies into our treatment. The KEYNOTE-522 trial [NCT03036488] showed that if wecombine pembrolizumab [Keytruda] with chemotherapy, that has significantly increased the number of women were able to cure of that higher-risk TNBC.11

Approval of neoadjuvant pembrolizumab in combination with chemotherapy for patients with high-risk, early-stage TNBC followed by single-agent adjuvant pembrolizumab by the FDA in 2021 was a signifi cant advancement for the treatment of patients with TNBC.12 Data from the KEYNOTE-522 trial were considered practice changing early on, showing a pathological complete response in 64.8% of patients treated with the regimen.11

Likewise, for HER2-positive breast cancer, we have seen the development of multiple drugs that target HER2, from trastuzumab [Herceptin] and pertuzumab [Perjeta], to ado-trastuzumab emtansine [T-DM1; Kadcyla], that have increased the number of women who were able to cure of their HER2-positive breast cancers, Sharifi said.

Slamon also commented on the proliferation of HER2-targeting therapies in addition to the expansion of other types of targeted agents, benefi tting patients in the TNBC space. [Since] our initial fi nding of HER2 and trastuzumab, now theres a ton of HER2 targeting trastuzumab deruxtecan [Enhertu] and emtansine [Kadcyla], margetuximab [Margenza]the list goes on and on of anti- HER2 therapeutics. Then there are new therapeutics for TNBC; they look at the TROP-2 target on tumor cells, and sacituzumab govitecan [Trodelvy] is the new therapeutic for that.13 As we identify new targets that we can approach with an antibody thatll attach to it, [it could be possible to] make an antibody- drug conjugate [ADC] to allow that antibody to go right to the target protein on the tumor cell and have it released internally and that takes away the systemic effect of the chemotherapy and delivers it right into the cell. Thats a whole new strategy thats coming into its own in a big way now, Slamon told TTO.

The phase 3 ASCENT study (NCT02574455) showed that sacituzumab produced a PFS and overall survival (OS) benefi t over physicians choice of chemotherapy in patients with relapsed or refractory metastatic TNBC. The median PFS with sacituzumab was 5.6 months compared with 1.7 months with chemotherapy. Median OS was 12.1 months with the ADC and 6.7 months with chemotherapy.13

The emergence of these newer targeted therapies has permitted a risk-based tailoring of neoadjuvant and adjuvant therapies in the non-metastatic breast cancer space, observed Sharifi . Another major development over the last 10 years, particularly for the [patients with] TNBC and HER2-positive breast cancers, is a shift towards neoadjuvant chemotherapy, which allows us to identify women with higher risk of recurrence after our standard pre-operative chemotherapy, and then add additional therapy after surgery to reduce their risk. For instance, that is how ado-trastuzumab emtansine is used in HER2-positive breast cancer, and there are other targeted options in this space, including olaparib [Lynparza] for women with germline BRCA mutations, she said.

We have also made great strides in precision oncology in the metastatic breast cancer space, with an expansion of different types of targeted approaches, including mutation-targeted inhibitors, immunotherapy, and ADCs. While all of these developments have helped patients live longer and better with metastatic breast cancer, I think ADCs are the most game-changing new development for treating metastatic breast cancer, Sharifi told TTO. As an example, the ADC trastuzumab deruxtecan, is a HER2-targeting agent [encompassing] trastuzumab linked to a chemotherapy that was initially found to be extremely effective for HER2-positive metastatic breast cancer, even in women who have had multiple prior treatments with different other agents. Even more importantly, however, it has recently been shown to be effective also in women who have low HER2 expression, who would previously have been classifi ed as HER2 negative.14 This has dramatically expanded the group of women with metastatic breast cancer who can benefit from trastuzumab deruxtecan to include what we are now calling HER2-low breast cancers, which are far more common than HER2-positive breast cancers. So thats been an important advance for us in the ADC space just in the last year, said Sharifi.

Data from the phase 3 DESTINY-Breast04 trial (NCT03734029) showed that patients with low HER2 expression can still possibly benefit from HER2-targeted therapy. The trial demonstrated a median progression-free survival (PFS) of 10.1 months with trastuzumab deruxtecan therapy vs 5.4 months with physicians choice of therapy in patients with HER2-low (IHC 1+/IHC 2+, ISH-) metastatic breast cancer who had received 1 to 2 prior lines of chemotherapy. The median OS was 23.9 months with trastuzumab deruxtecan and 17.5 months with physicians choice of chemotherapy.14 These findings led to the FDA approval of trastuzumab deruxtecan in this disease setting just this year.15

The Importance of Individualization

Turning to mutation-targeted therapies, this has also been an active area in metastatic breast cancer treatment in the past 5 years, including the first FDA approval of a drug targeting PIK3CA mutations, [which] are common in many types of cancer and found in almost half of women who have ER-positive metastatic breast cancer, where the drug alpelisib [Piqray] has been approved for women with this type of mutation, Sharifi told TTO.

Approval for alpelisib in breast cancer was supported by fi ndings from the phase 3 SOLAR-1 trial (NCT02437318), which showed that the PI3K inhibitor in combination with fulvestrant led to a median PFS of 11.0 months vs 5.7 months with fulvestrant in patients with PIK3CA-mutant, HR-positive, HER2-negative advanced breast cancer.16

patient with metastatic breast cancer should be getting molecular profi ling to identify possible targeted therapy options, and many patients will now have ADC treatment options that they may be eligible for at some point in their disease trajectory. For patients with localized breast cancer, I think weve also come a long way in being able to individualize therapy and avoid exposing patients to unnecessary [adverse] effects while also being able to augment treatment for patients who are at higher risk of recurrence and cure more women with this diagnosis, Sharifi said.

The basis of this personalized therapy derived from breast cancer-based research, observed Slamon. The gamechanger clearly was [the molecular advancements]. [When] looking at what is big in oncology, its this appreciation that originated in breast cancer and now has spread throughout the field of human oncology about this molecular diversity defining, a) different subtypes, and b) new potential therapeutic targets or pathways, he said.

Sharifi looks to the continued development of ADCs as a cancer treatment modality. Theres a real untapped well of potential targets that were just starting to explore in terms of developing new ADCs and combining them with targeted and immunotherapy approaches, and I think this will move the bar in how were able to combat treatment resistance, said Sharifi.

Slamons view of the future also comprises targeted strategies : As we identify more targets...therell probably be more and newer, perhaps even better, therapeutics than we have currently. Breast cancer has led this field.

REFERENCES:

1. Bettaieb A, Paul C, Plenchette S, Shan J, Chouchane L, Ghiringhelli F. Precision medicine in breast cancer: reality or utopia? J Transl Med. 2017;15(1):139. doi:10.1186/s12967-017-1239-z

2. Cocco S, Piezzo M, Calabrese A, et al. Biomarkers in triple-negative breast cancer: state-of-the-art and future perspectives. Int J Mol Sci. 2020;21(13):4579. doi:10.3390/ijms21134579

3. Low SK, Zembutsu H, Nakamura Y. Breast cancer: The translation of big genomic data to cancer precision medicine. Cancer Sci. 2018;109(3):497-506. doi:10.1111/cas.13463

4. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Trans Med Chir Soc Edinb. 1896;15:153-179.

5. Hou Y, Peng Y, Li Z. Update on prognostic and predictive biomarkers of breast cancer. Semin Diagn Pathol. 2022;39(5):322-332. doi:10.1053/j.semdp.2022.06.015

6. Nicolini A, Ferrari P, Duff y MJ. Prognostic and predictive biomarkers in breast cancer: past, present and future. Semin Cancer Biol. 2018;52(Pt 1):56-73. doi:10.1016/j.semcancer.2017.08.010

7. Cardoso F, vant Veer LJ, Bogaerts J, et al; MINDACT Investigators. 70- gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729. doi:10.1056/NEJMoa1602253

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A Decade of Breast Cancer at the Molecular Level: Pioneering Personalized Medicine - Targeted Oncology

Heidelberg, 18 October 2022 EMBO launches further funding and support schemes for life scientists at all career stages in eleven countries. The schemes include grants for researchers displaced by the military invasion in Ukraine or other armed conflicts.

Until the end of 2024, life scientists in or going to Croatia, Czech Republic, Estonia, Greece, Hungary, Italy, Lithuania, Luxembourg, Poland, Slovenia, and Trkiye (Turkey) can apply for the schemes. These countries are member states of the EMBC (European Molecular Biology Conference), the intergovernmental organization that funds the EMBO Programmes. The initiative aims to increase participation of scientists from across Europe in the programmes, especially in countries that currently benefit less from the programmes.

The new schemes and support offerings are:

These new schemes and support offerings are in addition to those launched previously:

Details of all schemes and offerings, including eligibility criteria and the application process, are availablehere.

All these schemes and support offerings are funded with means from EMBC.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

See the article here:

Increasing participation in the EMBO Programmes across Europe - EurekAlert

Cancer is a disease where the cells of the body grow uncontrollably and can invade other parts of the body. These cells can destroy healthy cells by blocking essential nutrients and changing the function of organs.

Cancer impacts millions of people in the United States alone. Treatment options have improved in recent decades, but many underlying mechanisms of cancer remain unknown.

A recent study published in Nature Structural & Molecular Biology explored a specific molecular pathway that may underlie several cancer types, including basal cell carcinoma of the skin, which is the most common form of skin cancer, and medulloblastoma, the most common brain tumor affecting children.

Understanding how this pathway works could open the door for new cancer treatment options.

In 2020, cancer was the second leading cause of death in the U.S. Experts are still working to understand what triggers and contributes to cancer development and growth.

Researchers have collected some data on risk factors for specific cancer types so that people can understand their risks and work to take preventative steps.

Treatment options for cancer have increased in recent decades, with more targeted therapies becoming available that cause less damage to the rest of the body. Cancer treatment can involve a combination of several treatments, such as radiation, immunotherapy, hormone therapy, or surgery.

To develop new treatments with greater success rates and fewer side effects scientists are working to better understand the biological mechanisms which can increase an individuals risk of developing the disease.

Studying what happens at the cellular and molecular levels can identify new targets for treatment.

Researchers involved in this study looked at a key signaling pathway in organ development, known as the Hedgehog pathway. Underactivity of this pathway has been linked to birth defects, while overactivation has been shown to drive certain cancers.

Study author Dr. Benjamin Myers, assistant professor in the Department of Oncological Sciences at the Huntsman Cancer Institute, University of Utah School of Medicine, explained the underlying mechanism of interest in this current study.

This study was focusing on a system in our bodies known as a signaling pathway. A signaling pathway is a bit like a telephone wire in our cells that helps relay important information from the outside of the cell to the inside, he explained.

The signaling pathway that we are studying, known as Hedgehog, is very important in helping our tissues and organs develop correctly. Also, errors in this signaling pathway can lead to birth defects or cancers, including some fairly common skin tumors and pediatric brain tumors, the study author further noted.

Researchers focused on the Smoothened protein (SMO). They found that the SMO protein physically blocks a key signaling enzyme in the Hedgehog pathway called the PKA catalytic subunit (PKA-C).

The lack of PKA-C causes the release of gene-regulating proteins which are usually inhibited and the promotion of the Hedgehog pathway.

Dr. Myers explained:

For many years, scientists knew that Hedgehog played all these critical roles in development and disease but didnt understand how the actual telephone wire worked what type of molecular signal was encoded, and how did it travel from the outside of the cell to the inside? Our study helps to resolve this longstanding mystery by revealing the underlying molecular basis for how Hedgehog signals travel along this telephone wire.

Dr. Santosh Kesari, director of neuro-oncology at Providence Saint Johns Health Center and chair of the Department of Translational Neurosciences and Neurotherapeutics at Saint Johns Cancer Institute in Santa Monica, CA, who was not involved in this study, offered a further explanation to Medical News Today.

This study elaborates on the mechanism of how these tumors grow when a signal on the surface of the tumor cell initiates a signaling program that makes these grow uncontrolled. They found a novel mechanism whereby hedgehog signaling goes through PKA-C to activate the pathway. This opens up a new understanding and possible a new drug target, he told us.

The study offered significant findings and is a critical step towards understanding an underlying mechanism in particular cancer development. However, it only utilized mouse and cellular models, which can only provide a certain level of information. Further research is going to be essential when it comes to translating this information into clinical practice.

Dr. Kesari noted: Future research will focus on confirming this signaling pathway and how it affects tumor growth. This pathway can be looked at as a target for drug development to try to prevent this activation of tumor growth program.

Ideally, the data from this study can help to forward the development of more targeted cancer treatments. Dr. Myers was optimistic about what they had found and what it could mean for the future.

Our study helps to explain at a molecular level how errors in Hedgehog signaling can lead to birth defects or cancer. Having this knowledge help scientists and clinicians understand these diseases at a more fundamental level. In the future, our research may enable new types of drugs to correct the faulty Hedgehog signaling events that occur in cancer and thereby provide therapeutic benefit to cancer patients in the clinic, he said.

This was very difficult in the past due to a lack of knowledge about how the Hedgehog pathway worked at a molecular level, but the insights provided by our study may help to realize this long-term therapeutic goal in the future, added Dr, Myers.

Excerpt from:

Skin and brain cancers: New discovery may help improve treatment - Medical News Today

For decades, medical cancer treatment has generally meant chemotherapy, radiation, or surgery, alone or in combination. But things are changing rapidly. Today, new approaches such as immunotherapies and targeted therapies are becoming available, with many more in research and development. In many cases, the new treatments are more effective, with fewer side effects.

Its an exciting time to be in cancer research and cancer discovery, said Colin Duckett, PhD, professor of pathology, interim chair of the Department of Pharmacology and Cancer Biology, and vice dean for basic science."

Were moving into this era where we have a new set of tools we can use to treat cancer.-Colin Duckett, PhD

Researchers in the Duke Cancer Institute (DCI) and across the School of Medicine are helping to create these new tools, fueled by the knowledge and experience of experts from a wide range of disciplines.

Indeed, cancer research has always been a team-based endeavor at DCI.

DCI was specifically created a decade ago to break down barriers between disciplines to stimulate collaborative research and multidisciplinary interaction, said DCI Executive Director Michael Kastan, MD, PhD, the William and Jane Shingleton Distinguished Professor of Pharmacology and Cancer Biology.

Adding fuel to the fire is the Duke Science and Technology (DST) initiative, which aims to catalyze and support collaborative research in service of solving some of the worlds most pressing problems, including cancer.

The new tools, though varied, all represent advances in personalized cancer medicine. Targeted treatments are chosen based on the genetic signature of a patients tumor. Some immunotherapies take personalization even further, by manipulating a patients own immune cells to create a treatment for that individual alone.

To match treatments to patients, the multidisciplinary Duke Molecular Tumor Board, led by John Strickler, MD, HS11, and Matthew McKinney, MD06, HS06-09, HS10-13, helps providers identify best practices, newly approved treatments, or clinical trials for advanced cancer patients based on genetic sequencing of their tumors.

In precision cancer medicine the right therapy for the right patient at the right time all these things come together, the targeted therapies, the immunotherapy, even standard chemotherapy, all of that is part of precision cancer medicine.-Michael Kastan, MD, PhD

Immunotherapy aims to harness the power of the immune system to fight cancer. That can mean activating the immune system, energizing exhausted immune cells, or helping immune cells find cancer cells by guiding them there or by removing cancers good guy disguises.

Dukes Center for Cancer Immunotherapy supports these efforts by identifying promising basic science discoveries and building teams to translate those ideas into treatments.

"There are so many world-class basic research scientists here making discoveries..."-Scott Antonia, MD, PhD

...discoveries that are potentially translatable as immunotherapeutic strategies, said Scott Antonia, MD, PhD, professor of medicine and the centers founding director. Thats what motivated me to come to Duke, because of the great opportunity to interact with basic scientists to develop new immunotherapeutics and get them into the clinic.

Antonia believes immunotherapy has the potential to revolutionize cancer treatment, but more work remains to be done to realize its promise. The proof of principle is there, he said, but still only a relatively small fraction of people enjoy long-term survival. If we can hone immunotherapeutic approaches, thats our best opportunity.

Among the most exciting immunotherapy work being facilitated by the center involves removing a patients own T cells (a type of lymphocyte), manipulating them in the lab to make them more effective against tumors, then injecting them back into the patient.

T cells can be manipulated in the lab in a number of different ways. In one approach, called CAR T-cell therapy, the T cells are engineered with an addition of synthetic antibody fragments that bind to the patients tumor, effectively directing the T cells directly to the tumor cells.

In another approach, called tumor-infiltrating lymphocyte (TIL) adoptive cell therapy, the subset of a patients T cells that have already managed to find their way into the tumor are extracted and then grown to large numbers before being returned to the patient. Antonia and his colleagues recently published a paper demonstrating the effectiveness of TIL expansion in lung cancer. Were now doing the preparative work to develop clinical trials using this approach in brain tumors, and our intention is to expand into many other cancers as well, he said.

Antonia points out that innovations in CAR T-cell therapy and TIL therapy happening at Duke are possible because of collaborations with scientists in an array of disciplines, including antibody experts like Barton Haynes, MD, HS73-75, the Frederic M. Hanes Professor of Medicine, and Wilton Williams, PhD, associate professor of medicine and surgery, at the Duke Human Vaccine Institute, and biomedical engineers like Charles Gersbach, PhD, the John W. Strohbehn Distinguished Professor of Biomedical Engineering at the Pratt School of Engineering.

Furthermore, clinical trials for these kinds of cellular therapies require special facilities to engineer or expand the cells, which are provided by Dukes Marcus Center for Cellular Cures, led by Joanne Kurtzberg, MD, the Jerome S. Harris Distinguished Professor of Pediatrics, and Beth Shaz, MD, MBA, professor of pathology. Its been a very productive collaboration highlighting how Duke is uniquely positioned to develop immunotherapeutic strategies, Antonia said.

Targeted therapies exploit a tumors weak spot: a genetic mutation, for example. The benefit is that the treatment kills only cancer cells and not healthy cells. The prerequisite is knowing the genetics and biology of the specific tumor, no simple task.

Trudy Oliver, PhD05, who joined the Department of Pharmacology and Cancer Biology faculty as a Duke Science and Technology Scholar, studies cancer development and the biology of tumor subtypes, particularly squamous cell lung cancer and small cell lung cancer.

Even within small cell lung cancer, there are subsets that behave differently from each other, she said. Some of the treatments shes identified are in clinical trials

Our work suggests that when you tailor therapy to those subsets, you can make a difference in outcome.-Trudy Oliver, PhD'05

Some of the treatments shes identified are in clinical trials.

Sandeep Dave, MD, Wellcome Distinguished Professor of Medicine, is leading an ambitious project to analyze the genomics of the more than 100 different types of blood cancer. His project will streamline the diagnosis of blood cancer and uncover potential therapy targets.

All cancers arise from genetic alterations that allow cancer to survive and thrive at the expense of the host, he said. These genetic alterations are a double-edged sword they allow these cancer cells to grow, but on the other hand they do confer specific vulnerabilities that we can potentially exploit.

Dave said his background in computer science, genetics, and oncology helped him as he designed the project, which uses huge datasets.

Weve done the heavy lifting in terms of tool development and methodology, which is ripe to be applied to every other type of cancer."-Sandeep Dave, MD

Cancer disparities are caused by a complex interplay of elements, including access to health care and other resources, institutional barriers, structural racism, and biology, such as ancestry-related genetics. For example, some genetic biological factors and social elements contribute to disparities in many types of cancer.

Cancer treatment is approaching this personalized space where patients are no longer treated with a one-size-fits-all paradigm."-Tammara Watts, MD, PhD

"Its becoming increasingly apparent that there are differences in outcome with respect to race and ethnicity, said Tammara Watts, MD, PhD, associate professor of head and neck surgery & communication sciences, and associate director of equity, diversity, and inclusion at DCI. The very broad hypothesis is that there are genetic ancestry-related changes that may play a critical role in the disparate clinical outcomes we see every day in our cancer patients.

For example, self-identified white patients with throat cancer associated with the human papilloma virus (HPV) have better outcomes compared to self-identified Black patients, even when controlling for elements such as health care access, education, and socioeconomic status.

Watts is collaborating with bioinformatics experts at DCI to try to identify significant differences in gene expression among the two groups.

Im trying to tease out differences that may be impactful for disadvantaged patients based on race and ethnicity, she said. But there could be differences that emerge that could be useful for designing targeted treatments for a broad group of patients.

Thats because a targeted treatment for a particular genetic expression that might occur more commonly in Black people would help all patients with that expression, regardless of race or ethnicity.

Watts is far from alone in doing cancer disparity research at DCI. Tomi Akinyemiju, PhD, associate professor in population health sciences, uses epidemiology to study both biological factors and social elements that contribute to disparities in many types of cancer.

Jennifer Freedman, PhD, associate professor of medicine, Daniel George, MD92, professor of medicine, and Steven Patierno, PhD, professor of medicine and deputy director of DCI, are studying the molecular basis for why prostate, breast, and lung cancer tend to be more aggressive and lethal in patients who self-identify as Black. Patierno, who has been a national leader in cancer disparities research for more than 20 years, leads the Duke Cancer Disparities SPORE (Specialized Program of Research Excellence), funded by the National Cancer Institute. The SPORE grant supports these researchers as well as other DCI teams working on cancers of the breast, lung, stomach, and head and neck.

One of the things that impresses me is that [cancer disparities research] is a high priority within DCI, said Watts, who joined the faculty in 2019. These groups are actively engaged and collaborating and asking the questions that will drive change for patients who have worse outcomes that are related to ancestry.

Even better than a cancer cure is avoiding cancer altogether.

At DCI, Meira Epplein, PhD, associate professor in population health sciences, and Katherine Garman, MD02, MHS02, HS02-06, HS09, associate professor of medicine, are looking to decrease the incidence of stomach cancer by improving detection and treatment of the bacteria Helicobacter pylori, which can set off a cascade leading to stomach cancer. Epplein and Garman, also funded by the Duke Cancer Disparities SPORE grant, hope their work will reduce disparities because H. pylori infections and stomach cancer are both more prevalent among African Americans than whites.

When preventing cancer isnt successful, the next best thing is to detect and treat early. A relatively new concept in cancer care is interception, which means catching cancer just as, or even just before, it begins.

The point is to prevent it from progressing to full blown malignancy, said Patierno. In other words, stop the cancer from getting over its own goal line.

Patierno envisions a future where patients with pre-cancerous conditions or early cancer could take a pill to halt cancer development without killing cells in other words, a non-cytotoxic treatment, unlike standard chemotherapy.

We know its there, but were not going to poison it or burn it or cut it out because all of those have side effects. Were going to find a non-cytotoxic way to prevent it from progressing. Thats the goal.-Steven Patierno, PhD

Read About Alumni Making a Differencein Cancer Research and Care:

Changing theStatus Quo: Lori Pierce MD'85

Treatingthe WholePerson:Arif Kamal, MD,HS12, MHS15

Targetingthe Seeds ofCancer Growth:Eugenie S. Kleinerman, MD75, HS75

A DiscoveryThat Comes Outof Nowhere:Bill Kaelin, BS79, MD82

Story originally published in DukeMed Alumni News, Fall 2022.

Read more from DukeMed Alumni News

See the article here:

Developing New Tools to Fight Cancer - Duke University School of Medicine

XBBa new, extremely immune-evasive Omicron variant surging in Singaporehasnt yet been detected in the U.S. But its child has.

XBB.1 was first detected in the U.S. on Sept. 15 and made up 0.26% of cases that were genetically sequenced over the past 15 days, Raj Rajnarayanan, assistant dean of research and associate professor at the New York Institute of Technology campus in Jonesboro, Ark., told Fortune. He cited data from GISAID, an international research organization that tracks changes in COVID and the flu virus.

Only 16 XBB.1 cases have been detected in the U.S. so far, and most have been found in New Yorkconsidered a bellwether state because of its volume of incoming international travelers and robust genetic sequencing capabilities, Rajnarayanan said.

XBB is a combination of two different Omicron spawns. It, along with BQ.1.1, is considered to be the most immune-evasive COVID variant so far, surpassing the immune-evasiveness of shared ancestor BA.5, which was dominant around the globe this summer.

Scientists, including top U.S. infectious disease expert Dr. Anthony Fauci, expect a fall and winter wave of cases in the U.S. that begins to surge in October and peaks in January. Its still unclear which COVID variant may fuel that wave. On Friday the U.S. Centers for Disease Control and Prevention announced that heavyweight Omicron spawn BQ.1 and BQ.1.1 are in the U.S., and quickly rising. With XBB present as well, the scene has been set for a potential battle royal between two formidable variants.

Compared to XBB, XBB.1 features just one small change to the spike protein, which the virus uses to attach to and infect cells. The impact of the alteration is unknown, according to Rajnarayanan.

Its one of multiple XBB offspring being eyed by variant trackers globally that are helping fuel Singapores wavedespite a significantly vaccinated and boostered population.

Rajnarayanan isnt worried about one variant in particular right now, as current Omicron spawn are all picking up similar mutations that confer advantages like increased transmissibility and additional ability to evade immune systems.

Hes keeping a close eye on XBB. But hes keeping a closer eye on BQ.1.1, which, along with parent BQ.1, was estimated to make up more than 11% of cases in the U.S. last weekthis on the first day the two variants were broken out into their own categories from ancestor BA.5.

BQ.1.1 is surging in New York and also rising in European countries like Germany, where Oktoberfest celebrations may have served as super-spreader events. Its extreme immune evasiveness sets it up to be the principal driver of the next U.S. wave in the weeks ahead,Dr. Eric Topol, a professor of molecular medicine at Scripps Research and founder and director of the Scripps Research Translational Institute, tweeted on Friday.

On Thursday, he told Fortune that scientists wont know to what extent it evades vaccine protection, if it does, until it reaches 30% to 50% of cases somewhere.

Its not going to wipe out vaccine efficacy, but it could put a dent in protection against hospitalizations and death, he said.

Both XBB and BQ.1.1 are known to escape antibody immunity, rendering useless monoclonal antibody treatments used in high-risk individuals with COVID. According to a study last month out of Peking Universitys Biomedical Pioneering Innovation Center in China, both escape immunity from Bebtelovimab, the last monoclonal antibody drug that is effective on all variants, as well as Evusheld, which works on some. And both could lead to more severe symptoms, the authors wrote.

The ability of XBB to evade immunity is extreme, approaching the level of immune evasion shown by SARS, a coronavirus that infected thousands and caused nearly 800 deaths in the early 2000s, the authors added.

BQ.1.1 and XBB are so distinct from other Omicron strains that they should be granted new Greek letter names, like Pi or Rho, by the World Health Organization, Topol told Fortune last week.

Whether the two strains eventually battle for dominance in the U.S.or anywhere elseremains to be seen. They may even find themselves sparring in one hostand the result could be a strain that combines the two, Ryan Gregory, a professor of evolutionary biology at the University of Guelph in Ontario, Canada, told Fortune. Or descendants of the two might find themselves battling it out instead.

With the viruss record rate of evolution, the possibilities are seemingly endless.

If people arent boosted and havent been infected in a little while, youre going to see lots of transmission, youre going to see direct competition, Gregory said, speaking of the highly immune-evasive variants. Were basically going to see them both move into whatever hosts are available.

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The XBB family of Omicron has landed in the U.S. Here's what it means for this fall's COVID wave - Fortune

In 2021, three Projects for Progress (P4P) teams set out to improve the quality of life in West Philadelphia: one by addressing the primary care needs of homeless and underserved people, one by revamping the Cobbs Creek Community Environmental Center, and one by addressing the COVID-induced learning gap in elementary school students and educators. An Oct. 17 event celebrated the work of these teams and their 2022 counterparts. Six P4P groups have received awards since the initiatives inception.

First awarded in 2021, the Projects for Progress are managed by Penns Office of Social Equity & Community, which distributed $100,000 each to three teams of Penn students, faculty, and staffworking to promote equity and inclusion in Philadelphia by addressing health care, education, and environmental justice.

For Caroline Watts of the Graduate School of Education, the awards timing was crucial. When the pandemic hit in March 2020, many students in the School District of Philadelphia were out of the classroom for more than a year. A joint team from theGraduate School of Education and the Netter Center for Community Partnerships worked to address this gap, wrapping Netters annual summer programming in an added layer of academic and mental health support. The award also funded school-year support for educators at 15 schools in West and Southwest Philadelphia, including professional development, algebra readiness clubs, and mental health consultation.

With the Projects for Progress award, we were able to put our ideas into action at a time when resources were urgently needed to help students and teachers return to in-person learning, Watts says. This award enabled us to respond to critical learning and development needs and to provide children with a joyful in-person experience after a long period of isolation.

Ricky Brathwaite, a Ph.D. student at the Perelman School of Medicine, is part of a 2022 P4P team that is working to lower the burden of cancer disparities in West Philadelphia. The award provides funding for cancer education and screening kits while helping the team demystify cancer research participation through conversation, all concentrated in West Philadelphia. It helps us change from their community to our community by actively reallocating resources through service to meet people where they are, Brathwaite says.

The group has partnered with other agencies and organizations to extend their reach, and plans to expand their mission beyond colorectal cancer to include HPV testing as new at-home tests become available, in addition to providing free breast and cervical cancer early detection at events with mobile health units. The group is looking to best serve the community with the work we do, Brathwaite says.

The additional groups in the 2022 P4P cohort include the Economic Justice Partnership, which trains first-generation college students, students of color, and high school students to do peer coaching on financial education, and The Public Schools as Equity Infrastructure Studio+, a collaborative partnership working to design and implement public school campus upgrades that embody a new system-wide vision for schools as equity infrastructure.

The 2023 applications will go live on Jan. 17. Applications are due by Jan. 29.

Evelyn Gotlieb, Wharton 2021 undergraduate, concentration in health care management and policy, minor in chemistry

Junduo Liu, College of Arts & Sciences 2022 undergraduate, double major in biochemistry and health & societies, minor in Bbioethics

Michael Hagan, College of Arts & Sciences 2022 undergraduate, major in neuroscience

Ian McCurry, Perelman School of Medicine 2022 doctor of medicine program

Deepti Tantry, College of Arts & Sciences 2022 undergraduate, major in neuroscience, minor in health care management

Mentor:Joseph Teel, Perelman School of Medicine associate professor of clinical family medicine and community health

Bridging Gaps and Building Capacity: Student and Educator Supports for School Reopening in Learning Network 2

Caroline Watts, Graduate School of Education director, Office of School & Community Engagement; senior lecturer, Professional Counseling Programs

Diane Waff, Graduate School of Education professor of practice; director, Philadelphia Writing Project

Zachary Herrmann, Graduate School of Education executive director, Center for Professional Learning

Marsha Richardson, Graduate School of Education senior lecturer, human development & qualitative methods

Regina Bynum, Netter Center for Community Partnershipsdirector of teaching and learning, University Assisted Community Schools

A Collaborative Initiative to Renovate and Optimize the Cobbs Creek Community Environmental Center

Erica DePalma, formerly of the Water Center research program coordinator, Earth and Environmental Science Department

Chinedu Ocek Eke, School of Engineering and Applied Science director for graduate students programming, Office of Diversity, Equity and Inclusion

Anna Balfanz, Netter Center for Community Partnerships senior research coordinator

Cooper Yerby, School of Arts & Sciences 2023 doctoral program in earth and environmental science

The Economic Justice Partnership:

Brian Peterson, director of Makuu: The Black Cultural Center

Khusi Shelat, Wharton 2023 undergraduate, statistics

Soloman Thomas, Wharton 2023 undergraduate, management/entrepreneurship & innovation.

An initiative to lower the burden of cancer in West Philadelphia:

Roderick Brathwaite, Perelman School of Medicine Ph.D. student, cell and molecular biology, cancer biology

Carmen Guerra, Perelman School of Medicine Ruth C. and Raymond G. Perelman Associate Professor of Medicine

Erin Hollander, Perelman School of Medicine MD/Ph.D. student, cell and molecular biology, cancer biology concentration

Claudia Melendez, School of Arts & Sciences 2023 undergraduate, neuroscience/international relations, chemistry minor

Michael Noji, Perelman School of Medicine Ph.D. student, cell and molecular biology, cancer biology concentration

Armenta Washington, Abramson Cancer Center and Perelman School of Medicineresearch coordinator senior, Office of Diversity and Outreach

Public Schools as Equity Infrastructure Studio+:

Anna Balfanz, Netter Center for Community Partnerships Academically Based Community Service coordinator

Ellen Neises, Weitzman School of Design executive director of PennPraxis and Laurie Olin Professor of Practice

Akira Rodriguez, Stuart Weitzman School of Designassistant professor, Department of City & Regional Planning

Elinor Williams, Graduate School of Education Ph.D. student, education policy

Corey Wills, Stuart Weitzman School of Design and School of Arts & Sciencesgraduate student, master of city planning, master of environmental studies

Visit theProjects for Progress websitefor more information,or emailprojectsforprogress@sec.upenn.edu.

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Projects for Progress, two years in | Penn Today - Penn Today

DALLAS Oct. 12, 2022 For the third year in a row, UTSouthwestern is ranked as the top health care institution globally by Nature Index for publishing high-quality research inall subjects and in the life sciences.

Joan Conaway, Ph.D.

We are incredibly proud of the outstanding work by our scientists and clinical researchers that is reflected in these Nature Index 2022 rankings, said Joan Conaway, Ph.D., Vice Provost and Dean of Basic Research at UTSW. Our discoveries impact multiple fields in basic science and are making a real difference in developing diagnostic and therapeutic applications for patients at our institution and beyond.

The Nature Index compiles affiliation information from research articles published in 82 premier science journals, providing perspective on high-quality scientific discoveries around the globe.

UTSW also ranked second globally this year among health care institutions in chemistry; among the top 10 in biochemistry and cell biology, earth and environmental, and physical sciences; and among the top 25 in neurosciences. Other peer institutions on the global listings include Massachusetts General Hospital, Mount Sinai Health System, Memorial Sloan Kettering Cancer Center, the University of Texas MD Anderson Cancer Center, and Brigham and Womens Hospital System in the United States; along with the Scientific Institute for Research, Hospitalization, and Healthcare in Italy, the West China School of Medicine/West China Hospital of Sichuan University in China, and Renji Hospital in China.

UTSW's ranking is a testament to the consistent strength and impact of our research community. Our scientists are currently leading about 5,800 research projects with nearly $610 million in support from the National Institutes of Health, the state of Texas, foundations, individuals, and corporations, said W. P. Andrew Lee, M.D., Executive Vice President for Academic Affairs, Provost, and Dean of UTSouthwestern Medical School, who holds the Atticus James Gill, M.D. Chair in Medical Science.

UTSW faculty members have received six Nobel Prizes, and its faculty includes 24 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, 16 members of the American Academy of Arts and Sciences, 14 Howard Hughes Medical Institute Investigators, and three recipients of the prestigious Breakthrough Prize in Life Sciences. The Medical Center houses one of HHMIs 12 principal laboratories nationwide, has four HHMI Faculty Scholars on campus, and has more than 100 early-career researchers, who have come to UTSW through the Medical Centers acclaimed Endowed Scholars Program in Medical Science, subsequently establishing themselves as leaders in their fields.

The UTSW Graduate School of Biomedical Sciences, with more than 1,000 predoctoral and postdoctoral students, educates biomedical students, engineers, clinical researchers, and psychologists. The Graduate School has two Divisions: Basic Science and Clinical Science, which together offer 11 programs leading to the Ph.D. degree Biological Chemistry; Biomedical Engineering; Cancer Biology; Cell and Molecular Biology; Clinical Psychology; Genetics, Development, and Disease; Immunology; Molecular Biophysics; Molecular Microbiology; Neuroscience; and Organic Chemistry. In addition, an M.S. degree and graduate certificate are offered in Clinical Science.

Dr. Conaway holds the Cecil H. Green Distinguished Chair in Cellular and Molecular Biology.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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UT Southwestern ranked top health care institution globally for published research by Nature Index - UT Southwestern