Translational Archives - Page 5 of 31

Daniel Wahl, MD, PhD

Brain cancers are typically fatal, even when patients undergo intensive treatment. While treatments have recently improved for many cancers, the last major treatment advance for glioblastoma (the most common aggressive brain cancer) was decades ago. Our research team is taking a new approach. We have discovered that aggressive brain cancers like glioblastoma often steal nutrients from the rest of the body. In this V Foundation-supported work, we will discover how brain cancers use these nutrients and whether blocking this nutrient uptake will slow brain cancer growth and improve treatment responses.

Hemn Mohammadpour, DVM, PhD

Funded in memory of Lawrence and Patricia Shook

Multiple myeloma (MM) is a type of bone marrow (BM) cancer that remains a significant challenge to treat, despite therapy advancements. In this study, we aim to explore a new approach to enhance the effectiveness of standard MM treatments. Our focus is on a specific type of immune cells called myeloid cells, that play a role in tumor growth and immune evasion in MM patients. We observed that MM patients have an increase of a particular type of myeloid cell that express on their surface, a molecule called CXCR2, in the BM and places where the cancer has spread to bone: (osteolytic lesions). The myeloid cells may contribute to MM resistance to treatment and to evasion of the body’s immune system. Based on these findings, we propose a clinical trial to test a drug called SX-682, which targets CXCR2-positive myeloid cells. We will investigate whether adding SX-682 to standard MM treatment will improve patient outcomes. Our trial will focus on MM patients whose cancer has come back after initial treatment. The primary goal of our study is to assess the safety and tolerability of SX-682 with standard MM treatment. Additionally, we aim to understand how SX-682 affects the immune environment within the tumor and in the blood. By targeting CXCR2-positive myeloid cells, we hope to enhance the body’s ability to fight MM, improving patient survival. Our study represents a promising step towards developing more effective therapies for MM by harnessing the body’s immune system to better combat this challenging cancer.

Humsa Venkatesh, PhD

High-grade gliomas represent the leading cause of brain cancer-related death in both children and adults. A fundamental shift in our approach to glioma therapy is thus in dire need. Though much of cancer research has focused on attacking the malignant tumor cells, our focus here is to target the surrounding tissue that provides growth cues for the cancer to thrive. I recently discovered that one important cue for pediatric gliomas is the activity of neurons within the brain. We found that pediatric gliomas grow at a faster rate in response to elevated nervous system activity. Our work has led us to the discovery that these tumors directly communicate with electrically active neurons by plugging into the neuronal network to receive growth signals. These studies highlight the unexplored potential to target neuron-glioma circuit dynamics for therapy. We propose to take a unique new approach to treating these cancers by interrupting the electrical activity across these cancerous circuits. We aim to reframe our understanding of these tumors by investigating how they integrate electrical inputs and hijack normal mechanisms of brain development. A comprehensive understanding of these dynamic network interactions may lead to new therapeutic interventions aimed at normalizing the tumor microenvironment.

Josephine Taverna, M.D.

Funded with support from the Onuschak Family in memory of Dave Onuschak, and from the Carol and George Toulas Family Foundation

One challenge of lung cancer treatment is that cancer cells thrive in a tumor ecosystem (or habitat) that protects them. This tumor ecosystem consists of immune cells, blood cells, connective tissue that allow lung tumors to grow and spread to organs (brain, bones, liver, lungs). We recently discovered that PD1, AXL and STAT3 signals in lung cancer serves as “on switches” that drive lung cancer growth, treatment resistance and spread to organs. More importantly, these cancer signals allow cancer cells to communicate with nearby cells for protection. We found that blocking PD1, AXL and JAK signaling can block communication between tumor and non‐cancer cells in tumorecosystem. Our research team would like to perform mouse experiments and clinical trial using drug combinations that turn off these signals and disable the tumor within its habitat, thereby preventing tumor growth and spread. This therapy could help improve survival for our patients with lung cancer.

Andrea Cercek, MD

Funded with support from Dave and Rhea Benson in honor of Angela Sbarra

The rates of rectal cancer are increasing in young adults. Treatment for rectal cancer includes chemotherapy, radiation, and surgery. These therapies can have a negative effect on the quality of life of survivors. Radiation can cause infertility and problems with bowel and bladder function, as well as sexual health. Up to one third of the patients need a permanent colostomy so they do not have normal bowel function. Due to these issues, there has been an interest in finding ways to improve treatment for rectal cancer so that radiation and/or surgery may not be necessary. One way we are trying to improve treatment of cancer, including rectal cancer, is with immunotherapy. Immunotherapy empowers the patient’s own immune system to fight cancer. When this happens, it is very effective. Funding from the V Foundation will support a clinical trial that will treat rectal cancer that is mismatch repair proficient with immunotherapy first. The project team believes that improved immunotherapies like Botensilimab (anti CTLA4) and Basltilimab (PD-1), and earlier treatment before the tumor has spread, will lead to responses. This research has the potential to change the treatment paradigm of all early-stage rectal cancers and omit radiation and surgery in those patients whose cancers disappear with immunotherapy and chemotherapy alone. This will be an important finding for patients’ quality of life. It will also teach us how to make the immune system work against cancers where it has not worked in the past.

Oriana Damas, MD, MSCTI

Funded in partnership with the Dolphins Cancer Challenge (DCC)

In recent years, colorectal cancer (CRC) has become the third most common and second most deadly cancer in the US. CRC is the leading cause of cancer death among Americans under 50 years old, but experts do not know why rates are increasing among young people. Moreover, we do not have a good way of detecting people who are at higher risk of CRC. These people should receive early monitoring and undergo extra measures to prevent CRC. How can we identify these at-risk individuals? We propose that certain bacteria cause the production of an enzyme (DUOX2) in the gut. High levels of this enzyme are found in people with gut inflammation and people with CRC. In the proposed research, we plan to test whether patients with different types of CRC have different levels of DUOX2. We expect that some CRC types will have higher levels than others. Next, we will try to identify the bacteria that lead to high DOUX2 levels. Discovering these bacteria may help to identify people at higher risk of CRC (people with higher amounts of these bacteria) and suggest new cancer treatments (ones targeting these bacteria). Finally, we will test whether drugs that are already approved for use in humans, along with other products of bacteria, can reduce levels of DUOX2 in the gut. Identifying these drugs may improve prevention and treatment for CRC.

Livia Schiavinato Eberlin, PhD

Nick Valvano Translational Research Grant*

Surgery is the main treatment option for patients with rectal cancer. During surgery, the surgeon’s main goal is to completely remove cancer tissue without leaving cancer behind. However, not all diseased tissue can be seen with the surgeon’s eye, especially after radiation when tumor and scar look similar. Because of that, it is hard for a surgeon to be certain that all cancer tissue has been removed on the anal side to help preserve the anus and avoid a permanent bag. The same problem happens for adjacent organs such as the pelvic nerves, pelvic sidewall, vagina or prostate that may appear to be affected. Consequently, 4-20% of patients have recurrence while 20-50% have postoperative complications. Currently, there are no technologies that can help surgeons identify cancer tissues within the rectum and nearby organs in vivo during surgery. Surgeons are thus faced with the difficult decision to excise questionable tissue that could be affected by cancer at the devastating expense of compromising critical tissue structures and quality of life. In our study, we will evaluate the MasSpec (MS) Pen technology for tissue identification in rectal cancer surgery. The MSPen provides the transformative capability of detecting molecules diagnostic of cancer in tissues in vivo, without tissue damage. We will refine the MSPen for rectal surgery and evaluate its performance in identifying rectal cancer and normal tissues. The MSPen has the potential to help surgeons achieve complete cancer removal and preserve normal tissues, thus improving treatment, outcomes, and quality-of-life for patients.

Gina Ogilvie, MD

Cervical cancer is highly preventable. However, it remains a health burden and is the fourth most common cancer in females around the world. Cervical cancer is caused by “high-risk” types of the human papillomavirus (HPV). Screening for cervical cancer using HPV is much more effective than the Pap test. However, HPV screening alone cannot determine if an HPV infection will resolve, or if it will progress to cervical cancer. We need to find better ways to identify the people with HPV who have the highest risk of cancer.

The microbiome of the vagina may play an important role in progression to cancer. Understanding more about the vaginal microbiome in those with high-risk HPV could help us determine when an HPV infection may resolve or when it may progress. This knowledge could lead to earlier and better treatment and prevent cervical cancer from developing.

This research will be done in British Columbia, Canada. We will determine the microbiome characteristics of an existing set of cervical samples. We will then link these characteristics to over 10 years of cervical cancer screening results. We will explore if certain microbiome characteristics can determine whether HPV progresses to cervical pre-cancer or if HPV will clear. These findings can lead to important advancements in HPV screening for cervical cancer. This study has strong potential to impact global cervical cancer prevention and treatment standards. The findings are especially important as screening programs around the world shift to HPV-based cervical cancer screening.

Gelareh Zadeh, MD, PhD, FRCS(C)

Funded by Hockey Fights Cancer™ Powered by the V Foundation

Meningiomas are the most common intracranial tumor in adults. While most meningiomas can be successfully treated with surgery, there are a significant proportion of cases that require the addition of radiation therapy to delay tumor recurrence. However, our current methods of selecting which patients should be escalated for radiation after surgery remain relatively imprecise, especially for intermediate-grade meningiomas that can behave in a highly variable manner. Molecular profiling, specifically DNA methylation of meningiomas has proven to be an effective and efficient method of providing additional information on these tumors that can be used to better predict whether they will or will not recur after surgery. However, whether a similar set of molecular signatures exist to predict whether a meningioma of any given patient will respond to radiotherapy after surgery remain to be determined. This V Foundation grant will enable us to 1) develop a clinically important predictor using specific molecular signatures of any given patient’s meningioma to tell us whether their tumor will respond to radiation, 2) test this predictor through a novel, real-time, molecular-pathology informed clinical trial, and 3) determine if the same signatures that can prediction response to radiotherapy in the tumor tissue can be used to non-invasively provide the same information through a simple blood test. Results from this study have the potential to dramatically improve the way we treat patients with meningiomas and will represent a significant shift forward in the field of neuro-oncology.

Xiao-Nan Li, M.D., Ph.D.

Funded by the Dick Vitale Pediatric Cancer Research Fund and the StacheStrong Foundation

Clinical outcomes in children diagnosed with high grade glioma and diffuse intrinsic pontine glioma remain very poor. Even with surgical resection, chemotherapy and radiation, most of the tumors eventually relapse. This is primarily because some cancer cells develop resistant to the therapies that doctors prescribe. For the past 50 years, the identities of these therapy-resistant cancer cells remain unknown. Difficulties of obtaining relapsed tumor tissues and limited availability of animal models are the major reasons why we still don’t have new treatment. With the strong support of patients and families, we have developed a panel of animal models by directly implanting brain tumor cells into the brains of immunodeficient mice. We can now use these models to mimic what happens in children but treating the animals with the similar drugs/radiations. These models are very helpful. Indeed, our preliminary study in a small number of models have identified a set of cells expression CD57 as candidate root cells as they were found before drug treatment, remain present after very extensive clinical treatment, and can even survive the most harmful environment with no oxygen and no nutrient. This exciting finding has promoted us to perform a detailed analysis using more animal models to confirm the extraordinary capacity of the CD57+ cells in resisting therapy induced cell king, to understand how they can survive current treatment, and to find new drugs and strategies to selectively kill these seed cells. Our ultimate goal is to find new cure for children with highly malignant gliomas.