Christine Chio, PhD is unlocking the mechanisms of an especially lethal form of pancreatic cancer, which is difficult to detect, and resistant to treatment. 
PDAC – or pancreatic ductal adenocarcinoma – is a highly aggressive cancer, one that is both difficult to detect and to treat; it accounts for more than 90% of pancreatic cancer cases. Dr. Chio and her colleagues are particularly interested in waste products of this cancer – called reactive oxygen species, or ROS – which can damage the structure of cells, and accelerate the spread of the cancer, accounting for much of its lethality. 
The work of her lab focuses on the mutations that cause this cancer, and why to date they have largely proven stubbornly resistant to treatment. Velocity support has funded this search for new knowledge, and helped bring new personnel on board, in the search for more effective interventions.

Eileen Connolly, MD, PhD, is researching why some cancers are resistant to radiation therapy, and how we can make those interventions more effective.  
High-dose radiation therapy, or HDRT, delivered as stereotactic body radiotherapy (SBRT), is often used as a cancer therapy, particularly in the metastatic setting – extremely precise, very intense doses of radiation are delivered to cancer tissue, while minimizing damage to healthy tissue. SBRT has a profound immunostimulatory effect on tumors – though in some patients, it can also cause an immunosuppressive response, which contributes to tumor regrowth. The goal of Dr. Connolly and her colleagues is to target this radiation even more precisely, for maximal effect in a tumor’s microenvironment.  
They are particularly interested in the Notch signaling pathway, crucial in how cells reproduce, and are differentiated into their function; the goal is to disrupt the further production of cancerous cells. Consequently, Notch inhibitors are being studied clinically for their potential use as cancer therapeutics. Preliminary data generated with funding from the Velocity grant show that a combination of HDRT, an immune checkpoint inhibitor (ICI) anti-PD1 antibody, and Notch inhibition using a γ-secretase inhibitor (GSI) AL101 results in synergistic inhibition of tumor growth that significantly prolongs survival in a mouse model of cancer. These findings have provided Dr. Connolly and her colleagues with the necessary elements to apply for larger grants to study the mechanism underlying the synergistic combination of Notch inhibition with HDRT and IC to improve anti-tumor response, with a goal to ultimately open a Phase I/II clinical trial of this triple combination. 

John C. Markowitz, MD, is studying the links between breast cancer and depression – and how to treat patients successfully, simultaneously, for both.

Breast cancer and depression unfortunately go together, with each disorder worsening the course of the other. Both are treatable, although when you’re depressed it may not feel that way. We know that people who develop major depression in the context of breast cancer get better with antidepressant medication or with brief evidence-based psychotherapy, but the two approaches have never been compared to one another. The Velocity Fellows funding has given Dr. Markowitz and his colleagues the opportunity to do so.

They are now three-quarters of the way through a randomized controlled 12-week tele-psychiatry trial, comparing treatment by Zoom with a serotonin reuptake inhibitor medication (venlafaxine or escitalopram) to Interpersonal Psychotherapy (IPT), and are looking to complete enrollment by the end of the summer. Thus far, patients who have remained in treatment have generally gotten better.

Dr. Markowitz and his colleagues have noticed that many women who have undergone treatment for breast cancer are reluctant to take another pill – even though antidepressant medication is generally very effective, side effects are typically mild and brief, and medication may offer some benefits (for example, for pain) that psychotherapy does not. They have just published an article in General Hospital Psychiatry about this “psychopharmaphobia,” and are developing an approach to reassure patients about these medications.

Laura Pasqualucci, MD and Riccardo Dalla-Favera, MD are investigating the mechanisms in the spread of a rare lymphoma and looking to turn these insights into targeted treatment to stop the growth of tumors.

Diffuse large B lymphoma – or DLBCL – is an aggressive cancer of the lymphatic system; over 18,000 cases are diagnosed each year. Drs. Pasqualucci, Dalla-Favera and their colleagues are elucidating the mechanisms by which this cancer mutates, in the hope of developing an intervention that can stop that mutation. They have also found that the tumors are functionally addicted to these mutations for their growth – so the hope is that, if these mutations can be slowed or stopped, the cancer will be as well.

Funds from Velocity have allowed these investigators to further elucidate the origins of this cancer; to share their work with colleagues in publications and at conferences; and to assemble the data necessary to make this work eligible for further funding, from the NIH and the Leukemia and Lymphoma Society.

Hee Won Yang, PhD is studying why some breast cancer patients develop resistance to a therapeutic treatment–called CDK 4/6 inhibitors–that have proven to be successful in other patients with similar diagnoses.

Stopping the growth of any cancer is always a therapeutic priority, and in combatting breast cancer, doctors have had success by using medicines that interrupt the process by which breast cancer cells divide and multiply. The goal here is to suppress two specific proteins – known as cyclic-dependent kinases 4 and 6, or CDK 4/6 – which, in cancer patients, can become overactive, causing cancerous cells to divide uncontrollably. The therapies to combat them, then, are known as CDK 4/6 inhibitors – and they have been successful in stopping the growth of breast cancers in some – but not all – patients. Dr. Yang and his colleagues are investigating why these interventions are successful in some patients, but not others; and have identified a predictive biomarker – that is, they are developing the capacity to predict in which patients this therapeutic intervention will work, and for whom it likely won’t.


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