Empowering individuals

Refining risk stratification

New approach to refining risk stratification for colorectal cancer patients

This study seeks to harness deep learning methods to identify unique patterns across colorectal cancer (CRC) tumor slides for improved disease classification using 300,000 images collected already from over 6,000 patients.

This will provide a novel addition to classic histopathology and molecular methods for improved treatment and management of CRC.

Link to Pathology University Bern

Lay Abstract

Colorectal cancer is the third leading cause of cancer-related mortality in Switzerland and despite improvements in therapy for patients with metastatic disease, the overall 5-year survival rate remains low, at 60%. Biomarkers for risk-stratification in patients with non-metastatic disease remain scarce. The tumor microenvironment, however, can provide a wealth of potential new biomarkers as it consists of a rich network of different types, frequencies and densities of cell types, which may also reflect the underlying molecular aberrations of the cancer. These interactions are complex and can only be comprehensively analyzed using computational methods. In this study, we use the histopathology images of colorectal cancer tissues to study these cellular interactions using artificial intelligence approaches, including deep learning. We identify cancers with particular molecular defects based on patterns within the tissues and study the impact of these patterns on patient outcome.

A combined budding

A combined budding / T-cell score in pT1 and stage II colorectal cancer(CRC)

Numerous immune cell types are found in CRC and have been linked to improved prognosis in CRC; especially T-cell infiltrates have been extensively examined as a protective biomarker.  This proposal aims to build on existing know-how and utilize geometric deep learning methods to create a combined tumor budding/t-cell scoring system.

The results are expected to have a direct impact on patient management and contribute to more precise treatment strategies in patient subgroups.

Lay Abstract

In colorectal cancer, the most important parameter for prognosis and determining patient management is tumor spread according to the Tumor-Nodal- Metastasis (TNM) classification. However, the TNM system may show considerable differences in tumors within the same stage. Therefore, additional biomarkers for a more personalized risk stratification in certain CRC patient groups are needed.
Tumor budding, namely single tumor cells and small clusters of tumor cells at the invasive tumor front, is such a biomarker. However, tumor buds do not account for other factors, such as the bodys protective response. Especially T-cells, a type of inflammatory cell, have been extensively examined as a protective factor. Our own preliminary data demonstrates that a combined assessment of tumor budding and T-cell infiltrates in CRC (termed the Budding/T-cell Score or BTS) may better reflect how aggressive a tumor is than either marker alone.
In this project, we want to further investigate the BTS using graph-based deep learning. On images of slides used to diagnose CRC, graph-based representations are created based on detected tumor buds and T-cells. We believe that this approach will be beneficial for the combined assessment of tumor buds and T-cells, because it captures not only the raw count of the cells but also their structural arrangement, which, we hypothesize, might play a central role for predicting important information for patient treatment. In a third step, geometric deep learning, which extends deep learning beyond the domain of Euclidean geometry, is applied to the graphs to predict clinical endpoints, such as survival time.

Voice quality after laser surgery

Voice quality after laser surgery versus single vocal cord irradiation

This proposal seeks to compare single vocal cord irradiation (SVCI) to transoral CO2-laser microsurgical cordectomy (TLM) on patient-reported voice quality in a prospective randomized multi-center open-label comparative phase III study.  This approach is promising to spare voice quality and thus improve quality of life.

Lay Abstract

Laser surgery and radiotherapy are well-established standards of care for unilateral stage 0 & I carcinoma in situ (Cais) and squamous cell carcinoma of glottic larynx (SCCGL). Based on meta-analyses, functional and oncological outcome after both treatment modalities are comparable. However, no properly conducted randomized trials comparing these treatments exist. The only such trial with the endpoint of voice quality had to be prematurely closed due to low accrual.
The traditional radiotherapy involves the treatment of the whole larynx. Recently, a new radiotherapy technique was introduced by a team of researchers from Netherlands, where the treated target volume consists of involved vocal cord and therefore 8 to 10-fold smaller than the target volumes used for traditional whole larynx irradiation. The treatment is reduced to 16 fractions which corresponds to 3 weeks and a day. The results of a prospective cohort (n=30) with single vocal cord irradiation (SVCI) were compared with the results of a historical prospective cohort previously treated with whole larynx radiotherapy (n=131) in the same institute. The median follow-up was 30 months. The voice handicap index (VHI) at all time points beginning from the 6th week after SVCI was significantly superior to the same time points with conventional radiotherapy. Moreover, a comparable local control with SVCI (100%) vs. conventional radiotherapy (92%) was reported at two years, p=0.2412.
Based on this information, the investigators' main aim is to compare SVCI to Transoral CO2-Laser Microsurgical Cordectomy (TLM) with the main focus of patient-reported voice quality.

Relapsed or Refractory Acute Myeloid Leukemia

A Phase I/II Trial of 8-Chloro-adenosine in Relapsed or Refractory Acute Myeloid Leukemia

This phase I/II trial will assess the safety and efficacy of 8-Chloro-Adenosine (8-Cl-Ado), a new therapeutic small molecule that is preferentially toxic to cancer as opposed to normal cells. It has shown potent anticancer activity against leukemia cells and has been very well tolerated in an earlier human clinical trial evaluating safety for different blood cancer.

Lay Abstract

We developed a novel drug, called 8-chloro-adenosine (8-chloro-ado), that can prevent the RNA in leukemia cells from replicating, causing the cells to die. We have conducted a phase 1 clinical trial of this drug in patients with recurrent/refractory acute myelogenous leukemia (AML), where we administered it directly into the blood vessels for one hour daily for five days. The protocol was based on our compelling studies in cell cultures and animals showing that cell lines and patient leukemia cells are sensitive to this drug at low concentrations. Twenty heavily previously treated, older (average age 68), poor risk patients (eight with previous myelodysplastic syndrome (MDS) and eight with previous bone marrow transplant) were admitted to the trial. Of note all patients leukemia cells from their bone marrow taken before treatment with 8-chloro-ado were sensitive to the drug. Potential heart toxicity was witnessed with the one-hour infusion and with FDA approval, the infusion length was changed to four hours daily for five days to help reduce side effects. As a result, five of the six patients treated at the current dose showed a dramatic but short-lived reduction in leukemia cells in their blood. We have now demonstrated increased killing of leukemia cells by combining 8-chloro-ado with the approved AML drug venetoclax in cell lines and animal studies and plan to advance this combination in our next clinical trial. This will allow us to treat patients with AML earlier in their disease course, ultimately improving health outcomes for these patients. 

A Phase I Immunotherapy Study Using HER2-CAR T Cells for Malignant Glioma

A Phase I Immunotherapy Study Using HER2-CAR T Cells for Malignant Glioma

The central hypothesis is that CAR T cells targeting cell surface antigens will eradicate diffuse tumor cell populations. This hypothesis will be tested in phase I clinical trial in 11 patients over a duration of four years. The study will assess the safety and determine the recommended phase II dosing plan for loco-regional administration in 3 routes.

Lay Abstract

High-grade malignant glioma (MG), including glioblastoma multiforme (GBM-grade IV), presents obstacles that have blocked attempts to improve patient outcomesthe five-year overall survival rate of patients with GBM is just 5.5%. In the majority of cases, standard therapies are not effective in eliminating malignant GBM cells, which spread microscopically throughout the brain. Long-term disease control requires therapy that targets and eliminates diffusely located cancer cells, and this represents an unmet medical need. Chimeric antigen receptor (CAR)engineered T cells may provide a safe and effective way to treat MG. In this patient-specific immunotherapy, the patients T cells are isolated and engineered to specifically target tumor cells. We have developed a CAR T cell therapy for MG that targets human epidermal growth factor receptor 2 (HER2), which is found on a high percentage of MG tumors, but not on normal brain cells. Our central hypothesis is that CAR T cells targeting the cell surface specific to MG will eradicate cell populations in patients with MG. Thus far, 15 patients have received HER2-CAR T cells, 14 have completed the standard prescription of three doses with no adverse reactions, 10 patients have gone on to receive additional optional doses, and four patients remain on study awaiting CAR T cell infusion. This treatment is significant as it addresses the poor outcomes of patients with MG, and the findings may contribute to improved safety and effectiveness of CAR T cell therapy in brain and other cancers.

Development of Alternative Ablation Device

Development of Alternative Ablation Device for Cervical Pre-Cancer Treatment

The trial aims to demonstrate that the cure rates of the CryoPen and the thermoablator are non-inferior to the cure rate of CO2-based cryotherapy; determine patient acceptability of each therapy type by actively assessing side effects and monitoring pain levels related to treatment; evaluate screening methods one-year post-ablation by comparing the sensitivity of low-cost HPV screening tests, HPV DNA genotyping tests, cytology, and biopsies. 

Lay Abstract

In 2018, the World Health Organization (WHO) called for action towards achieving the global elimination of cervical cancer. A strategy for achieving this goal was ratified by member states in August 2020. The WHO plan calls for an aggressive approach of vaccination against the human papillomavirus (HPV), the single cause of cervical cancer, and screening and treatment of precancerous lesions caused by HPV infections before they progress to invasive disease. In low- and middle-income countries (LMIC), which bear 90% of cervical cancer incidence globally, it is estimated that these goals will not be reached until 2120 a century from now. One way to markedly shorten this timeline is to provide widespread high-performance testing for cervical precancer followed by immediate treatment of any abnormalities. Currently, the most commonly used method of treatment of pre-cancer is using gas-based cryotherapy. Although gas-based therapy is effective, it is difficult to have widespread scale-up because gas tanks are heavy and difficult to transport, tanks need to be refilled and equipment requires maintenance to function properly. The purpose of this study is to examine alternatives to gas-based cryotherapy including non-gas-based cryotherapy (funded by NIH) and thermal ablation (funded by rising tide). This is a randomized controlled trial which will compare cure rates of high-grade cervical precancer after treatment with cryotherapy and the 2 alternative approaches. Upon successful completion of this trial low-cost, portable, effective treatment for cervical pre-cancer will be clinically validated. Clinically validated tools for treatment of pre-cancer are crucial for worldwide elimination. 

Career Pathway in Symptom Management

Career Pathway Grants in Symptom Management

The goal of this program is to recruit and retain individuals committed to conducting symptom management research. This unique approach will support young physician-scientists at a critical time in their academic careers when they transition from training to principal investigators and begin to set up labs of their own.

The recipients of the 2020 Conquer Cancer Rising Tide Foundation for Clinical Cancer Research Career Pathway Grants in Symptom Management are:

Antonio Di Meglio, MD, Institut Gustave Roussy$
A Comprehensive Bio-behavioral Approach to Tackle Cancer-related Fatigue in Breast Cancer Survivors
Mentor: Ines Vaz-Luis, MD, PhD

Nicole Grogan, MD,  University of Michigan Cancer Center
A Single Center Phase 2 Trial to Evaluate Use of Cannabidiol (CBD) to Treat Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS) in Early Stage Breast Cancer Patients
Mentor: Norah Lynn Henry, MD, PhD

Daniel Lage, MD, MSc, Massachusetts General Hospital
A Care Transition Intervention for Hospitalized Patients with Advanced Cancer
Mentor: Jennifer Temel, MD

Risa Wong, MD, Fred Hutchinson Cancer Research Center
SuPPORT: Screening for Psychosocial Distress in Prostate Cancer and Offering Referrals for Treatment
Mentor: John Gore, MD, MS

Link to 2020 Conquer Cancer Rising Tide Foundation for Clinical Cancer Research Career Pathway Grants

Phase III randomized clinical trial

Phase III randomized clinical trial for stage III epithelial ovarian cancer -  OVHIPEC-2

This clinical trial is a multi-center phase III study including 8 countries and 538 patients. This study is led by the Netherlands Cancer Institute and the funding requested is to cover the cost of pharmacovigilance.

Lay Abstract

Over 75% of the patients with epithelial ovarian cancer are diagnosed with advanced disease that has spread beyond the ovaries to the peritoneal surface (stage III-IV). Optimal treatment for advanced disease involves surgery and six cycles of intravenous chemotherapy. The overall 5-year survival is 30-40% for patients with advanced stage disease. The chance of getting recurrent disease within two years is 80%. To improve outcome, additional strategies for these patients are warranted. Supplement with hyperthermic intraperitoneal chemotherapy (HIPEC) to interval debulking surgery (IDS) improve the progression free survival and overall survival in patients with stage III ovarian cancer. The impact of HIPEC in addition to primary debulking surgery (PDS), is still uncertain.
Objective: The primary objective of this study is to evaluate the effect of HIPEC on overall survival when added to primary cytoreductive surgery in patients with FIGO stage III ovarian cancer who are eligible for primary cytoreductive surgery resulting in no residual 
Study design: An international, randomized, un-blinded, phase III trial, including 538 patients with ovarian cancer stage III for whom upfront surgery is feasible.
Intervention: PCS with HIPEC is performed with cisplatin (100mg/m2) for 90 minutes at a temperature of 41-42oC in the abdominal cavity at the end of surgery. 
Main study endpoints: Primary endpoint is overall survival. Secondary endpoints are recurrence-free survival, time to subsequent anticancer treatment, toxicity and morbidity. Time to second subsequent anticancer treatment, quality of life analysis and economic- and cost evaluation are exploratory endpoints.

Central Pathology Review

Central Pathology Review of FFPE tumor blocks within the POSITIVE study

The primary goal of the POSITIVE trial is to determine if a two-year interruption of endocrine therapy results in a significantly higher breast cancer event rate in comparison to a historically estimated control rate if no interruption occurred. Samples have been collected from 90 % of the patients enrolled in the POSITIVE clinical trial and funding is required for processing and analysis.

Lay Abstract

Pregnancy is a major concern for premenopausal breast cancer survivors. Conception after breast cancer in women with hormone receptor positive (HR+) disease is affected by the standard 5-10 years of anti-hormonal therapy during which pregnancy is contraindicated. 
The POSITIVE study evaluates whether it is safe, in terms of risk of breast cancer recurrence, to temporarily interrupt adjuvant endocrine therapy to attempt pregnancy. It is also an exceptional opportunity to investigate the biology of breast cancer in young patients, a subset that is well-known to be biologically distinct, yet poorly studied particularly at the molecular and genomic level.  
The Central Pathology Review is a crucial component of multicenter tumor trials. Therefore, within the POSITIVE Study, it is integral to centrally collect patient tumor tissue and review tumor biological characteristics (such as ER, PR, Ki67 and HER2) alone and in combination with clinical-pathological parameters (grade of tumor, size of tumor, nodal status and patient age). The aim is to evaluate whether treatment interruption for some women with high-risk tumors may be detrimental and whether pregnancy might modify the risk of cancer relapse. 
The data obtained will therefore permit individualized assessment of patient outcomes according to the biologic characteristics of the tumor as well as a better understanding of the overall results of the POSITIVE study. In addition, the results of the Central Pathology Review will enable future molecular subtyping in order to better tailor treatment in this population and help future patients fulfill their motherhood wish, without risking breast cancer relapse.

Targeting eIF4A in melanoma persistent cells

Targeting eIF4A in melanoma persistent cells to prevent resistance

By combining BRAF+MEK inhibitors with eIF4A inhibitors the team has managed to kill the persistent cells and prevent the emergence of mutant resistant clones in vitro. The objective of this grant is to translate this strategy to the clinic.

Epigenetic therapy to sensitize patients

Epigenetic therapy to sensitize patients with advanced NSCLC to chemotherapy and immunotherapy targeting reversal of immune tolerance

The team had found in an earlier study that epigenetic therapy appears to sensitize patients to subsequent treatments including chemotherapy, and very excitingly, to immunotherapy, targeting reversal of immune tolerance. 

Neurocognitive & Quality of Life (QOL)

Neurocognitive & Quality of Life (QOL) in proton/photon pediatric brain tumor survivors

This retrospective study seeks to directly compare the long-term health outcomes between two pediatric brain tumor survivor cohorts treated with proton and photon radiotherapy.  This study involves a direct comparison of neurocognitive and health-related quality of life outcomes among brain tumor survivors treated with proton radiation at Massachusetts General Hospital (MGH, Boston, MA, USA) and survivors treated with photon radiation at Emory University/Childrens Healthcare of Atlanta (CHOA, Atlanta, GA, USA).  While radiation is an essential component of curative treatment, it can also contribute to a variety of late adverse health effects. This research will guide future radiation treatment decisions and advocate for access to the radiation technology that maximizes the quality of survivorship in childhood brain tumor patients.

Link to the cancer survivor study

Lay Abstract

Brain tumors are the most common solid cancers affecting children and adolescents. Medulloblastoma and ependymoma are common brain tumors that require treatment with radiation following surgical resection. While radiation is an essential component of curative treatment, radiation to the developing brain contributes to adverse health effects that can impair quality of survivorship. There are two major types of external-beam radiation: photon-based and particle (proton) radiation. Both radiation modalities are alike in their cure rates and biological effectiveness. However, compared with photons, proton radiation has better physical properties that localizes the radiation dose in the tumor target while sparing proximal normal tissues. We need to follow patients for a long time after treatment to determine if the dosimetric advantages of protons translate to an improvement in health outcomes. Supported by the Rising Tide Foundation, our study compares neurocognitive function and quality of life between brain tumor survivors greater than five years out from treatment with protons at Massachusetts General Hospital or with photons at Emory University Hospital. Participants complete a comprehensive clinical evaluation, neurocognitive assessment, and PedsQL survey. DICOM radiation treatment plans are collected to assess dosimetric differences to the brain and its sub-regions. We hypothesize that patients treated with protons will have better neurocognitive outcomes and quality of life scores than patients treated with modern photon radiation due to the ability of protons to spare more normal brain. Our research will guide future treatment decisions and advocate for access to the radiation technology that maximizes quality of life for survivors.

CD38-targeted immuno-PET

CD38-targeted immuno-PET imaging to prevent myeloma relapse

This phase I/II proposal will assess the dose and safety of a combination of an antibody currently used for the treatment of multiple myeloma with a radiolabel element that will generate images on PET scan for disease detection and treatment response monitoring.

Aspirin as an Adjuvant Therapy

ASCOLT STUDY (phase III): Aspirin as an Adjuvant Therapy for Colorectal Cancer

This phase III trial will assess the effectiveness of daily aspirin against placebo control in stage 2 and 3 patients. This is an international collaboration led by researchers in Singapore, UK, and Australia, and involves 50 sites in 11 countries across Asia.

Lay Abstract

The ASCOLT study is a clinical trial that is being undertaken to investigate if aspirin can the recurrence of colorectal cancer after surgery and chemotherapy.  The trial is a large international phase 3 study involving more than 60 hospitals in more than 12 countries and has recruited more than 1500 patients to date.   In the past decade, there have been numerous trials exploring the use of new chemotherapy agents and biological agents in the prevention of colorectal cancer recurrence.   These trials have failed to show benefit.  Aspirin is now considered an important prospect and together with the AddAspirin study, the attention of the scientific community is on ASCOLT - to deliver important information on the utility of aspirin in this setting.  Numerous observational studies have demonstrated the benefit of aspirin in early stage resected colorectal cancer.  A positive finding in ASCOLT will change the practice of colorectal cancer and save many lives globally.  Because aspirin is cheap and costs a penny, the repurposing of aspirin as a cancer treatment drug will open a large avenue for its use in colorectal cancer and potentially other cancers.

Improving accessibility of clinical cancer trials

Improving the accessibility of clinical cancer trials results to patients

This project seeks to take the existing patient engagement program at SAKK to the next level, by including patients in the process from trial design through to dissemination of results upon completion of the trial. Indeed, within the framework of this project, with the support of the SAKK Patient Advisory Board, SAKK wants to make the results of the trials accessible to patients, their relatives, and the public. In this way, SAKK wants to make clinical cancer research transparent and accessible to everyone.

Link to the Patient Advisory Board of SAKK

Lay Abstract

Close exchange with cancer patients and patient organizations is vital for the further development of new and improved cancer therapies that seek to improve the chance of a cure and patients quality of life.
SAKK therefore set up the Patient Advisory Board in November 2015 with the aim of gaining a better understanding of the needs of cancer patients and their families, in order to improve SAKK research projects. 
The Patient Advisory Board currently has eight members with a very wide range of experience and background knowledge. The members of the Patient Advisory Board undertake further training on an ongoing basis and contribute with their valuable knowledge to our projects.
For example, the Patient Advisory Board participates in the development of information for patients and in this way makes these documents easier to understand.
In the coming years, the Patient Advisory Board will also be involved more intensively in the planning and development of trials to include the needs of patients in the trial design. The first pilot projects have started and are being refined continually. 
Another important project is the preparation of lay summaries of SAKK trial results, in order to make the results understandable and available for the patients and the public. Pilot projects to gather experience in writing lay summaries for various SAKK trials are ongoing. 
Twice a year, the Patient Advisory Board organizes the SAKK Patient Forum. This public event, focusing on a different cancer-related topic each time, allows patients and interested individuals to learn more about the latest research findings and provides an opportunity to ask questions and participate in related discussions.
The Patient Advisory Board is contacted frequently by external partners (the federal government, research institutes, healthcare organizations and universities), and asked to actively work on their projects to include the patients point of view and needs.

TAXIS

TAXIS

Targeted axillary dissection (TAD) is a new technique that has recently been developed for patients with initially positive nodes undergoing systemic treatment before surgery. It combines the selective removal of nodes that are localized under imaging guidance.

The main objective of this trial is to show that TAD is non-inferior to conventional axillary lymph node dissection (ALND) in terms of disease-free survival of breast cancer patients

Lay Abstract

Worldwide more than 450000 patients are diagnosed with breast cancer every year. It accounts for one-third of all cancer diagnoses among women and causes more than 130000 deaths per year. Until the mid-nineties, the complete removal of all lymph nodes in the armpit was the standard treatment for patients with breast cancer, causing massive morbidity in one-third of patients with decreased quality of life. Over the past 25 years, this radical operation was slowly abandoned in patients without tumor signs in their lymph nodes. However, it is still standard of care in patients with cancer detected in their lymph nodes before surgery. 
This study addresses the questions if radical surgery of the lymph nodes can be safely replaced by a novel limited surgery concept called tailored axillary surgery in combination with radiotherapy, and if this new treatment combination results in better quality of life compared to the standard radical procedure. One half of the 1500 patients will undergo radical surgery and the other half will receive the new combination treatment. 
If this study is positive, it is likely to establish a new worldwide treatment standard with less side effects and better quality of life, while maintaining the same efficacy as radical surgery. This would help to decrease surgical overtreatment of patients with breast cancer on a global scale.

Bedside diagnosis of bloodstream infections

Bedside diagnosis of bloodstream infections (BSI) in leukemia

A novel diagnostic method, activated filter paper, uses cellulose as a cheap and abundant resource to immobilize DNA probes. Combined with iron-oxide bead detection, the natural brown color of the beads allows detection by the naked eye.

Extended pelvic lymph node dissection

Extended pelvic lymph node dissection vs. no pelvic lymph node dissection for intermediate- and high-risk prostate cancer

This phase III randomized trial proposes to study the benefits of performing extended pelvic lymph node dissection in a group of intermediate- and high-risk prostate cancer patients.

Link to Article

Reduced-intensity radio-chemotherapy

SAKK 01/18: Reduced-intensity radio-chemotherapy for stage IIA/B seminoma

The main objective of this trial is to conduct a single-arm, multicenter, prospective phase II trial testing different combinations of radiotherapy and chemotherapy based on the results of the current RTFCCR grant to reduce long-term toxicity.

Lay Abstract

Every year around 450 men in Switzerland develop testicular cancer, which is the most common type of cancer in men aged between 18 and 35. About half of those tumors are seminomas, most of which diagnosed with the tumor confined to testis and cured by removal of the affected testis. Around 15% of all patients do however present with disease which has spread to lymph nodes in the abdomen and pelvis, thus classified as having stage II disease and requiring further treatment. Standard therapy for a stage IIA or IIB seminoma is chemotherapy or radiotherapy. The two standard treatments are not usually combined. Although these treatments are extremely effective, they are intensive and bear the risk of long-term side-effects such as damage to the heart, blood vessels, kidneys, intestines and the inner ear, or the development of a second cancer. As the patients are often young, it is particularly relevant to reduce the risk of these side-effects as much as possible. The trial SAKK 01/18 is thus examining a new therapeutic approach: the combination of radiotherapy and chemotherapy, with a much weaker form of each therapy being used. This combination is designed to produce high rates of local control (by means of radiotherapy) and the eradication of micrometastases (by means of chemotherapy). Additionally, the trial aims to investigate how treatment affects the patients quality of life. SAKK 01/18 is the follow-on project to the completed trial SAKK 01/10 trial. The trial is running in Switzerland and Germany and 135 patients will be included.

Multimodal Intervention

A randomized, open-label trial of a Multimodal Intervention versus standard care in cancer patients with Cachexia

This multinational, phase III clinical trial seeks to investigate the hypothesis that a multimodal intervention delivered during chemotherapy in the advanced lung or pancreatic cancer is effective in preventing and/or delaying cancer cachexia, and as a consequence, will improve weight, food intake, physical function and quality of life.

If proven positive, the proposed cachexia intervention can be immediately adopted into current practice and can be easily implemented across the healthcare system to become the new standard of care.

Anti-Osteoclast Therapy

Anti-Osteoclast Therapy as an Adjuvant in Treatment of Chondrosarcoma

This is a single-arm, open-label phase Ib clinical trial. 15 patients will receive 1 dose of zoledronic acid, followed by surgery 21 days after this dose. A second dose will be given 3 weeks after the surgery and patients will be monitored thereafter for 5 years.

Lay Abstract

Chondrosarcoma is a rare invasive cancer that affects bones and large joints. Extensive surgical resections with wide margins are necessary to cure this disease and surgeries can lead to significant morbidity. Radiation and chemotherapy have been largely ineffective for primary disease or for locally recurrent and metastatic disease. A pharmacologic agent that can potentially lead to function preserving surgical treatment, fewer local recurrences, and better control of systemic disease, would help improve the overall quality of life. Zoledronic acid is a widely used agent for treatment of metastatic cancer to the bone and to treat osteoporosis. Our pre-clinical studies have shown that zoledronic acid may help control the local destruction of bone by chondrosarcoma. Hence, we are conducting a clinical trial repurposing zoledronic acid by giving a dose prior to standard of care surgical resection and evaluating its impact on the resected tumor specimen. A second dose is given post operatively and time to local or metastatic recurrence as well as overall survival will be determined. The study is ongoing and 11 out of planned 15 patients have been enrolled. We hope to use this information to design a larger trial using zoledronic acid as an adjuvant therapy.

Walking Intervention for Symptom Elimination

WISE STUDY: Walking Intervention for Symptom Elimination under aromatase inhibitor therapy

This multicenter, randomized, intervention is composed of a 24-week home-based walking program starting at the onset of AI treatment. This involves  continuous moderate intensive walking outdoors for 30 mins, 5 days a week.

350 breast cancer survivors at the onset of adjuvant AI therapy will be randomized to the intervention or control group.

Link to the study
Link to Clinical Trials

Lay Abstract

Background:
Approximately 70-80% of all breast cancers are hormone receptor-positive. After tumor removal, these patients are recommended anti-hormonal therapy, with the use of an aromatase inhibitor (AI) being standard of care in postmenopausal women. AI-therapy can cause side effects ranging from disturbing to debilitating, especially joint/muscle pain and stiffness, but also fatigue, hot flashes, etc. 
Research Question:
The benefit of physical activity on manifested muscle/joint pain and stiffness under AI-therapy is well established. The purpose of our patient focused trial is to investigate whether physical activity has a preventive effect on side effects of AI-therapy.
Trial Intervention:
Patients are randomly allocated at the beginning of an AI-therapy to either an intervention arm (consisting of walking outdoors continuously for at least 30 minutes a day, 5 days a week for 24 weeks) or a control arm (no specific recommendation regarding physical activity). Patients in both arms wear a wrist-worn activity tracker with customized display (intervention arm: feedback about activity performed; control arm: no feedback).
Aim of the Trial:
The aim of this trial is to investigate if a simple outdoor walking intervention, beginning at the start of AI-therapy, can prevent muscle/ joint pain and stiffness and can positively affect symptom burden and quality of life in general.
Follow-Up:
During a follow-up phase of 1.5 years, the trial will assess whether the trial shows a lasting effect on pain, treatment adherence, an active lifestyle, and quality of life in general in the intervention arm compared to the control arm.

Liquid biopsies in early diagnosis

Liquid biopsies in early diagnosis of colorectal cancer

Based on recent developments by the team, this study aims to investigate the potential of using liquid biopsies for the early detection of colorectal cancer. 

Albeit liquid biopsies have been studied for some time, the novelty in the proposed approach lies in the ability to examine DNA methylation changes in addition to mutations in cancer genes.  This combined method has the potential to advance plasma cfDNA (circulating free DNA) testing.

Lay Abstract

Colorectal cancer is a curable disease if diagnosed early; however, patients with metastatic disease have poor treatment outcomes. Current available technologies to detect cancer are either invasive or can fail to detect cancer when it is present. Liquid biopsy is, on the other hand, a minimally invasive blood draw that can allow for the detection of oncogenic mutations and epigenetic changes such as DNA methylation in cancer DNA. Small fragments of tumor DNA that are shed in the blood are detected and analyzed using cutting-edge technology which can be used to create a cancer-specific profile. In this study, we aim to use different approaches to analyze liquid biopsies for the detection of colorectal cancer early in the course of disease before it has spread to other organs. We are investigating the utility of DNA mutational and methylation profiling using samples from liquid biopsies in different colorectal cancer cohorts (high risk patients without evidence of cancer, patients with early-stage disease, and patients with no evidence of disease after surgical removal of metastatic tumors) to determine if we can identify patients who are at high risk of disease occurrence or recurrence. Patients who are identified as high risk using this technology may benefit from earlier treatment intervention which can improve the outcomes of cancer management.

Optimizing Neurofeedback

Optimizing Neurofeedback to Treat CIPN

This project proposes to determine the optimal dose for the number of neurofeedback sessions to alleviate Chemotherapy-induced peripheral neuropathy (CIPN) and examine  predictors to determine who will best respond to neurofeedback using EEG brain signatures.

Link to the profile of Sarah Prinsloo

Lay Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is often a side effect of cancer treatment and can diminish a patients quality of life (QOL) by affecting everyday activities such as driving a car, putting on clothing, using utensils, and walking. CIPN also leads to treatment delays, dose reductions, and chemotherapy discontinuations which negatively affect treatment outcomes. Only two therapies have been shown to be effective to treat CIPN, neurofeedback (NFB) and duloxetine. Neurofeedback is a treatment that is customized to the individual, relatively inexpensive, non-invasive, and provided alongside conventional medicine. It is a reward system comprised of a brain-computer interface where participants are taught to change activity in brain regions that contribute to symptom perception. In our prior studies of NFB to treat CIPN, we found that patients with CIPN can learn to control activity in brain areas that are associated with CIPN, leading to QOL improvements such as restoration of normal exercise and recreational activities. This project aims to address three major obstacles to clinical improvement in CIPN symptoms. First, this project will help us understand CIPN at the level of individual brain function and will explore neurofeedback training in conjunction with duloxetine to maximize benefit to patients. Second, we will also discover the optimal amount of neurofeedback sessions needed to result in long-term relief of CIPN in a large group of participants and across socioeconomic groups. Lastly, this project will provide valuable information on the interplay between pain perceptions, treatments, and brain function. 

ECHO Telementoring

ECHO Telementoring to Improve Quality Palliative Care in Underserved Areas

Based upon preliminary data, this study aims to transform palliative care in the low-middle countries of India, Kenya, Ghana, and South Africa and elevate the standard of care in these regions.

Link to the Profile of Sriram Yennu

Lay Abstract

Patients with advanced cancer frequently experience severe multiple physical, emotional symptoms. These are associated with major morbidity in cancer care, poor quality of life, and impact overall survival. Their family members also experience physical and emotional distress. At the same time, patients and their families need to discuss the goals of care and to participate in advance care planning. These issues are even more urgent in medically underserved regions of low middle-income countries. Provision of access to quality palliative care can address these needs effectively. One of the main reasons is the lack of health professional education, training and support to health care providers taking care of this vulnerable patients. There is a great need to train the physicians, nurses, volunteers helping the patients with life limiting illnesses (palliative care clinicians) with skills required to provision of quality palliative care. We are proposing a collaborative ECHO (Extension for Community Healthcare Outcomes) telementoring project between the MD Anderson Cancer Center, Aga Khan University(Kenya), Korle-Bu Hospital (Ghana), University College Hospital(Nigeria), Tata Memorial Hospital  (India), and The African Cancer Institute (South Africa). The Palliative ECHO will consist of one-hour, twice monthly teleECHO clinics with participants ECHO. We will also examine the effects of ECHO on patient quality of life symptoms and caregiver experience over a period of 1 year.

Correlative studies of an open label Phase 1 study

Correlative studies of an open-label Phase 1 study in diffuse intrinsic pontine glioma (DIPG)

Based on previous studies and preliminary data, a phase 1 clinical trial of ONC206 is scheduled to start at the University Childrens Hospital Zurich. This trial is designed as a multi-arm trial based on different disease stages to enable the largest possible population to access ONC206. The proposal seeks funding for the correlative study of this clinical trial.

https://dipgcenter.ch/

Lay Abstract

There is an urgent need to develop and evaluate new therapies for children with brain tumours given their high mortality rates. This is particularly true for Diffuse Midline Gliomas (DMGs), which include Diffuse Intrinsic Pontine Gliomas (DIPGs), which affect over 2,000 children and young adults in the US and Europe every year. Sadly, despite decades of research, there are no effective treatments for this disease and over 90% of children die less than 2 years from being diagnosed. 
Promising drugs and treatment strategies are emerging, but they require extensive research at the preclinical stage. This is both to understand the mechanisms of action of these drugs, but also to identify clinically relevant predictive biomarkers of drug efficacy. Clinically relevant predictive biomarkers allow us to gauge, in real time, how well they will respond to treatment. 
Our project's aim is to assess tumor response to therapy.  Such studies will allow for designing more effective therapies for patients diagnosed with DMG. Our study is designed as a multi-arm trial based on different disease stages to provide access for the largest possible population of patients. This trial offers a new and promising agent to children in Europe where little to no innovative therapies are available, and limited clinical phase 1 trials are open. The results of our study will have a global impact on treatment strategies for children suffering from DMGs.

Early diagnosis

Early diagnosis and treatment of pre-leukemia

Currently, there is no reliable method to identify which patients with age-related clonal hematopoiesis (ARCH) will develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Based on preliminary data, the investigators propose to identify and treat high-risk individuals with ARCH, before they have developed the disease.

Lay Abstract

Acute myeloid leukemia (AML) has a long latent period of years before its aggressive and deadly clinical presentation. This latent period is characterized by the clonal expansion of preleukemic hematopoietic stem and progenitor cells (preL-HSPCs) carrying recurrent leukemia related somatic mutations. Spliceosome machinery mutations (SMMs) occur many years before AML, and accurately predict the progression to AML. As such, they are considered promising targets for preventive interventions. 
Our aim was to reveal an Achilles heel of cells that harbor the SRSF2 mutation, as well as the mechanistic role of this weak point. For this, we established 5 cell lines (MARIMO, K562, OCI-AML2, OCI-AML3 and MOLM14) in which we inserted the SRSF2 mutation using CRISPR that have served as platform for our overarching research goal.  Using these lines, we conducted a drug screen that resulted in the discovery of 39 potential molecules which demonstrated selectivity against the SRSF2 mutation. These hits included ROCK pathway inhibitors (ROCKi). The top performing ROCKi molecule was RKI-1447 with an IC50 value of roughly 100nM in the SRSF2 mut lines. Therefore, we chose RKI-1447 for the final validation step and screened its selectivity against five different biological replicates from each of the cell lines. We discovered that both OCI-AML2 and MOLM14 cell lines carrying SRSF2 mutations were significantly more sensitive to ROCKi compared to the WT isogenic line and specifically to RKI-1447. We then stained MOLM14 carrying SRSF2 mutation and  WT for Actin and Tubulin. Results demonstrated a unique phenotype observed in the SRSF2 mutant cell lines, which was aggravated by the addition of ROCK inhibitors. Cells carrying the SRSF2 mutant had a significantly more indented and lobulated nuclei. While we have established that ROCKi are effective against SRSF2 mutant cells, it remains crucial to understand why they are active.

Prevention of myeloid cancers

Prevention of myeloid cancers by understanding their pre-clinical evolution

This study will assess the genetic sequencing of stored blood samples from two patient groups to increase the knowledge about the pathway and changes cells suffer from pre-leukemia to leukemia, supporting the development of novel clinical concepts. Based on preliminary data, the investigators propose to identify and treat high-risk individuals with ARCH, before they have developed the disease.

Lay Abstract

The myeloid malignancies are a group of related cancers, including the myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Collectively, they affect 10 per 100,000 individuals per year and in most cases they are incurable. We and others identified the phenomenon of clonal hematopoiesis (CH), the expansion of a hematopoietic stem cell (HSC) and its progeny driven by leukemia-associated somatic mutations. CH is thought to be the precursor of most myeloid malignancies and we recently reported that certain characteristics of CH make it more likely to progress to one of these cancers. However, our ability to identify high risk individuals remains limited and insufficient for use in clinical/screening programmes. In this research programme funded jointly by the Rise Tide Foundation and the Leukemia and Lymphoma Society, we will perform detailed studies of the behaviour or CH over years/decades and develop new approaches to enhance our predictive ability and give us new insights into the factors driving CH towards leukaemia. We hope that our work will enable us to build the foundations of future approaches for early interception and prevention of myeloid cancers.

Phase 2 Study of PARP inhibition

Phase 2 Study of PARP inhibition and Anti-PD-L1 Therapy in BRCAmt TNBC

The clinical trial to which this proposal is attached is a randomized, open-label phase II trial exploring the effects of the anti-PD-L1 human monoclonal antibody atezolizumab with the PARP inhibitor Veliparib either alone or in combination in 100 patients with BRCA1/2 TNBC.

This grant will evaluate the mutational load, neoantigens, and anti-tumor immune effects of PARP inhibition and immune-stimulation and determine the possible connection between the biomarkers and patient performance after treatment.

Lay Abstract

Within the past decade, the growth of immunotherapy as a method to treat cancer has been astounding. However, while new immunostimulatory therapies have shown great success in the treatment of many types of breast cancer, not all types of cancer respond. A major challenge remains identification of mechanisms to effectively treat the majority of patients with so-called "non-inflamed" breast tumors. Work in the laboratory has shown that the DNA repair ability of a tumor may impact its potential for immune recognition and sensitivity to immune therapies. We hypothesize that enhanced DNA damage and cell death induced by DNA damage repair inhibition in tumors will also enhance anti-tumor immune responses. To examine this, we are conducting a clinical trial exploring the DNA damage repair inhibitor olaparib either alone or in combination with the human monoclonal antibody atezolizumab in patients with BRCA1/2 mutated locally advanced or metastatic non-HER2-positive breast cancer. In addition to producing a prominent clinical advancement, the Rising Tide award is allowing us to perform experiments to demonstrate fundamental concepts linking DNA repair, specific genomic landscapes, and anti-tumor immune response.  Ultimately, the results from this study have the potential to impact patient care by supporting the clinical development of a novel and biologically driven treatment combination to treat breast cancer.

Phase 2 Study of the PARP Inhibitor Olaparib

Phase 2 Study of the PARP Inhibitor Olaparib in IDH1/2-mutant solid tumors

To conduct a comprehensive series of correlative studies in tumor biopsies to identify which patients with IDH1/2 tumor mutations respond best to the DNA repair inhibitor, Olaparib.

Lay Abstract

Our collaborative research group at Yale recently discovered that tumors with mutations in two key metabolism-related genes, IDH1 and IDH2, induce exquisite sensitivity to DNA repair inhibitors. In particular, the DNA repair inhibitor, olaparib, was recently FDA-approved for the treatment of ovarian cancers with gene mutations that induce a similar sensitivity. In this proposal, we will perform a clinical trial which will test whether olaparib is effective against tumors with IDH1 and IDH2 mutations. We will perform a comprehensive series of correlative studies in tumor biopsies, in order to identify which patients respond best. This study represents a true bench-to-bedside endeavor, and it leverages the best Yale science with the goal of improving the lives of cancer patients.

Predictors of response to neoadjuvant therapy in melanoma

Clinical stage III melanoma, defined as patients with RECIST measurable, clinically detected nodal disease with or without in-transit metastases, represents a high-risk population with poor outcomes. Despite recent advances in adjuvant medical therapy, only 40% of clinical stage III BRAFV600E/K mutant melanoma patients treated with adjuvant dabrafenib and trametinib (DT) are relapse-free at 3 years. Thus, there is a strong need for new, more effective therapies for these high-risk patients.

Lay Abstract

Clinical stage III melanoma patients have poor outcomes when treated with upfront surgery and adjuvant therapy. Neoadjuvant, or pre-operative therapy, can potentially improve outcomes for this high-risk patient population. Researchers at MD Anderson Cancer Center and the Melanoma Institute of Australia have recently reported that approximately 50% of clinical stage III melanoma patients with BRAF V600 mutated disease achieve a pathologic complete response (pCR) or complete melanoma death, after exposure to neoadjuvant dabrafenib and trametinib (DT) treatment. Patients who do have pCR have improved survival outcomes compared to those that do not have a pCR. We do not understand which features will predict development of pCR but have identified preliminary molecular, immunological and pathologic data in pre-treatment tumors we believe may be predictive of long-term outcomes. Additionally, while pCR patients are less likely to develop relapse than non-pCR patients, there are still some pCR patients who relapse, and we believe there are distinct features in these patients surgical samples that determine subsequent relapse risk. Finally, patients who do not achieve a pCR are at higher risk of developing CNS metastases at time of relapse. We believe there are features in their tumor specimens which evolve over the course of therapy and identification of these factors will predict the risk of CNS relapse. Together, these studies aim to inform mechanisms of treatment response and resistance to BRAF targeted therapy, will enhance the field of neoadjuvant therapy, identify risk of CNS metastasis formation and ultimately improve melanoma patient outcomes.

TAXIS: Austria

The main objective of this trial is show that targeted axillary dissection (TAD) is non-inferior to conventional axillary lymph node dissection (ALND) in terms of disease-free survival of breast cancer patients. This phase III multicenter trial will be performed within the Austrian Breast & Colorectal Cancer Study Group and is being led by Prof. Walter Weber from the University Hospital Basel and seeks to support 250 patients in Austria.

Lay Abstract

The removal of all lymph nodes in the armpit through a conventional surgical method called axillary dissection has been standard care for patients with breast cancer for almost a century. In the nineties, the sentinel lymph node procedure, which involves the selective removal of the first few affected lymph nodes, was introduced in clinical practice. Today, conventional axillary dissection is still performed on many women with breast cancer that has spread to the nodes. It is the cause for undesired complications (morbidity) in the form of lymphedema, impairment of shoulder mobility, sensation disorders and chronic pain in as much as one third of all women undergoing the procedure.
The TAXIS trial will evaluate the optimal treatment for breast cancer patients in terms of surgery and radiotherapy. In particular, it will investigate the value of tailored axillary surgery (TAS), a new technique that aims at selectively removing the positive lymph nodes combined with axillary radiation. TAS combines the sentinel procedure with the removal of palpably suspicious nodes. It is a promising procedure that may significantly decrease morbidity in breast cancer patients by avoiding surgical over-treatment.
This trial has the potential to establish a new worldwide treatment standard with hopefully less side effects and a better quality of life, while keeping the same efficacy as provided by radical surgery. Tailored refinement of axillary surgery may herald an exciting era of reduced morbidity for breast cancer patients.

OLIGORARE - Stereotactic body radiotherapy in addition to standard of care

Based upon a strong scientific rationale, this proposal seeks funding to support a randomized phase III clinical trial investigating the addition of stereotactic radiotherapy to the standard of care treatment for patients with oligometastatic rare cancer. To this end, the primary objective of this clinical trial is to assess if the addition of SBRT improves overall survival (OS) as compared to standard of care treatment alone in patients with oligometastatic rare cancers.

Lay Abstract

Metastatic cancer can range from a single metastasis to widely disseminated metastases, making it the leading cause of cancer death. Oligometastases are considered an intermediate state between locoregional cancer and widespread metastases with a limited number of lesions and organs involved. Retrospective studies have shown that aggressive metastasis-directed therapy (surgery or radiation) added to standard of care systemic therapy achieved long-term survival or even cure in about one quarter of the patients. Evidence is mostly based on the common cancer sites: lung, colorectal and prostate cancers. It has however been proposed that this intermediate oligometastatic cancer stage may also exist in other cancer types, opening a curative window for many more cancer patients.
The 1945-OligoRare is an academic clinical study led by the EORTC in 6 countries in Europe (BE,CH,IT,DE,FR,UK) with a transatlantic collaboration with British Columbia Cancer Agency in Canada. It will be the first study to use the stereotactic body radiotherapy -SBRT- approach (targeted radiotherapy) in cancers where the oligometastatic state is uncommon, thus where data is severely lacking. Patients with oligometastatic cancer, including all solid cancer types except lung, breast, colon and prostate cancer will be eligible. 
Its primary objective is to assess if the addition of SBRT improves the overall survival compared to the standard of care treatment alone, in eligible patients with a maximum of 5 oligometastatic lesions. A total of 200 patients will be recruited over a period of 5.5 years.

Further information can be found here

SHortening Adjuvant PHoton IRradiation for Breast Cancer: The SAPHIRe Trial

Regional node irradiation (RNI) is a relevant component of treatment for breast cancer. There are multiple reasons why women do not receive curative RNI including fear of developing radiation-induced lymphedema and the inconvenience and cost of receiving five to six weeks of daily radiation treatment. The central hypothesis is that a shorter (3 week) RNI inclusive treatment regimen will provide equivalent cancer control, will reduce treatment toxicity, and will improve the convenience of RNI when RNI is indicated.

Lay Abstract

Women found to have breast cancer in their lymph nodes are often advised to receive radiation therapy to the lymph nodes to decrease the chance of cancer recurrence and improve survival.  Because of the length of treatment (at least five weeks) and the side effects of treatment (tiredness, arm swelling, and skin and tissue changes), some women who may benefit from radiation therapy do not receive it.  
An innovative shorter-duration radiation treatment regimen that delivers larger daily doses of radiation to the lymph nodes (called hypofractionation) may allow women to get the radiation they need while reducing the duration and toxicity of treatment.  The SAPHIRe trial (Shortening Adjuvant PHoton IRradiation) is a randomized, clinical trial of shorter-duration (three-week) versus standard-duration (five-week) radiation therapy in 842 patents receiving radiation therapy to the lymph nodes for invasive breast cancer conducted at academic and community practices across the United States.  The women who choose to take part in this trial will be assigned to one of these two treatments and will complete questionnaires about their side effects, physical function, quality of life, and financial well-being. They will also be evaluated for treatment complications, development of arm swelling (lymphedema), and cancer status. The trial is designed to demonstrate shorter-duration radiation to the lymph nodes provides similar cancer control while reducing the side effects and burden of treatment.
The development of a less toxic, less costly, more convenient, shorter-duration regimen is expected to reduce the burden of treatment and increase the utilization of curative radiation.

High fiber diet to enhance the microbiome in immunotherapy

Patient outcomes in metastatic melanoma, the most deadly of common skin cancers, have improved dramatically with the approval of immune checkpoint inhibitors (ICI). Nonetheless, not all patients benefit from these therapies and actionable strategies to enhance the effectiveness of ICI are urgently needed. This study seeks to develop a deeper understanding of the role of a whole foods, plant-based, fiber-rich diet on the microbiome and anti-tumor immunity in patients receiving immunotherapy.