Research Programs
Prioritized Research Programs in Cancer
Overview of need, interventions and approach to validation: Six hundred thousand patients in the US die annually from cancer despite receiving "standard of care" treatments, many of which are limited in efficacy, are quite toxic and expensive. Thus, there is considerable room for improvement.
The Morningside Center's research efforts in cancer are laser-focused on practical, affordable, and immediately implementable interventions that can be utilized in both academic and community oncology practice settings, thus ensuring that its work has immediate and widespread impact on patients at any phase of their cancer journey, from initial diagnosis through treatment and into survivorship. The interventions that Morningside explores are financial orphans, ideas not being pursued by the pharmaceutical industry due to lack of sufficient financial incentive.
The Morningside Center plans to validate the most promising financial orphan interventions by identifying them, writing and funding clinical trials. The hope is that the data generated from such studies will change cancer care guidelines. This process will inevitably require substantial time and financial resources.
Due to the wide availability of financial orphans, the Center believes that there is another path to gather evidence and influence guidelines: namely that cancer patients should discuss these interventions with their healthcare providers, carefully assessing individual risks and benefits to determine if any represent appropriate options for their specific clinical situation even in the absence of definitive randomized study clinical data or inclusion in national guidelines. For this purpose, a dedicated registry, open to all cancer patients in the US, will be established to capture real-world data from these and other cancer treatments, creating a valuable learning platform that can provide an early efficacy signal for both patients and physicians on what works and what does not. Such an approach will capitalize on the emergence of precision medicine by tailoring therapy to each individual’s case. This approach is complementary to clinical trials and one that may help to prioritize interventions for such studies.
Scientific framework: The Center's cancer focus is on the treatment of solid tumors both in the metastatic context as well as for prevention of cancer recurrence in surgically resectable disease (secondary prevention). Primary cancer prevention is not a priority due to the long timeline and cost of such studies.
The Center prioritizes treatments that fit into one or more of the following conceptual scientific frameworks, namely interventions that:
- Dampen the (typically immunosuppressive) injury response that occurs following surgical resection or after cytotoxic therapy
- Boost anti-tumor immunity guided by the steps of the cancer immunity cycle
- Kill cancer cells by increasing "stresses" on a cancer cell or blocking one or more stress adaptation pathways
- Optimize efficacy and reduce toxicity through smarter treatment dosing and scheduling
These approaches are not mutually exclusive and are elaborated on below.
Countering the Injury Response
Cancer has been aptly characterized as "a wound that does not heal", partly because solid tumors contain populations of dying cells that continuously trigger wound-healing responses. Moreover, conventional cancer therapies including surgery, chemotherapy, and radiation therapy inevitably cause additional cell injury and death, initiating the canonical injury response cascade.
This physiological response, while necessary for normal tissue repair, unfortunately promotes cancer through multiple mechanisms. Besides the creation of an immunosuppressive environment through recruitment of certain cell types (Tregs, MDSCs and M2 polarized macrophages, in particular), numerous growth factors foster the repair process: these promote tumor dissemination and activate dormant micrometastases of any remaining viable cancer cells, potentially undermining the beneficial effects of the primary treatment. Thus, blocking one or more aspects of the injury response should lead to more effective cancer treatment. Though there is some preclinical and clinical data to support this idea, it remains relatively under-explored.
Fortunately, the injury response can be effectively modulated by targeting 4-5 key molecular pathways integral to this process. Importantly, numerous non-cancer medications already exist that block these pathways, including non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines, antiplatelet agents, sympathetic nervous system blockers, and others. The injury response is an immunosuppressive state unless the wound is non-sterile. Thus, a unifying characteristic of these interventions is that they heighten anti-tumor immunity and will likely synergize with checkpoint blockade immunotherapy.
For cancers amenable to surgical resection, the most significant clinical challenge is preventing disease recurrence. Injury response modulators can be strategically employed for a short period of time during the perioperative period to prevent systemic recurrences. One challenge is to do this while preserving normal tissue repair functions. An example is the recent randomized control study in pancreatic cancer.
Moreover, recent clinical investigations have demonstrated that immunotherapy in the form of immune checkpoint inhibitors (ICIs) administered in the neoadjuvant (pre-operative) setting can significantly reduce recurrence rates e.g. in lung cancer. The fundamental goal is to maintain the immune system in a heightened state of cancer surveillance during the post surgical period, which is known to be an immunosuppressive state. Consequently, interventions that might enhance the efficacy of checkpoint immunotherapy for metastatic disease (see below) should be considered for implementation in the surgical setting. Not surprisingly, there is some overlap between those interventions and the treatments cited in the previous paragraph.
Injury modulators should also be effective in the metastatic disease i.e. serve to increase the efficacy of diverse treatment modalities including chemotherapy, radiation therapy, targeted molecular therapies, and immunotherapy, all of which cause tissue injury. Much remains to be done in this general area.
Boosting the Immune System
Immunotherapy has revolutionized cancer treatment and is now employed in nearly half of metastatic cancer cases across multiple tumor types and in an increasing number of surgically resectable cases to prevent cancer recurrence. Unfortunately, immunotherapy is not uniformly effective, with response rates varying significantly between cancer types. Moreover, immune related adverse events are common, and sometimes severe and even life-threatening.
The Morningside Center has identified several promising interventions that may enhance the effectiveness of existing immunotherapeutic approaches, especially those utilizing checkpoint blockade of the PD-1/PD-L1 axis. The key framework being evoked here is that of the cancer immunity cycle which spells out the sequence of events necessary for optimal immunotherapy. These interventions include (a) certain non-cancer drugs e.g. beta-blockers and antihistamines, (b) adjusting time of ICI administration (AM appears to be better) and scheduling of ICIs (e.g. delaying administration after chemotherapy), (c) using approved cancer drugs such as cyclophosphamide and capecitabine in low doses to decrease the number and/or function of immunosuppressive cell populations such as Tregs and MDSCs, (d) carefully monitoring and optimizing blood levels of certain vitamins (D) and minerals (Mg) that impact immune function, (e) implementing specific dietary modifications (e.g. fiber intake) and (f) administering an mRNA Covid-19 vaccine a few days before or after starting ICIs. Importantly, these interventions act on different parts of the cancer immunity cycle. The human data on these interventions is largely retrospective but there is extensive supporting animal tumor model studies suggesting causation and not just correlation and some human data in the form of case reports or series or phase I/II studies. A list of some of these interventions – as well as what to avoid - is detailed in numerous Morningside Center blogs.
Cytotoxic Treatments that work by increasing Cancer Cell Stress or Blocking Stress Adaptation Pathways
Cancer cells deploy sophisticated strategies that facilitate their survival within the harsh microenvironment characteristic of solid tumors, where hypoxia, nutritional deprivation, and reactive oxygen species generation present significant challenges to cellular viability. Other adaptation responses include the elaboration of cytokines that lead to the accumulation of immune cells that create an immunosuppressive environment. The Morningside Center believes in therapeutic approaches designed to either intensify one or more of these environmental stressors and/or inhibit the adaptive mechanisms that allow cancer cells to withstand these challenging conditions. Importantly, many of these adaptive pathways can be targeted using repurposed medications with established safety profiles, offering cost-effective and immediate means to potentially enhance treatment efficacy while minimizing additional toxicity.
Optimize Efficacy and Reduce Toxicity Through Smarter Treatment Dosing and Scheduling
Historically, many cancer treatments, particularly cytotoxic chemotherapies, were developed under the paradigm of maximizing tumor cell kill. This approach has led to the widespread adoption of maximum tolerated dose (MTD) regimens, which often result in significant treatment-related toxicities. The Morningside Center is actively investigating alternative dosing strategies, including metronomic therapy, which involves administering smaller, more frequent doses of chemotherapeutic agents.
This metronomic approach has demonstrated promising results in preclinical models and early human studies, often achieving reduced toxicity profiles, lower medication costs, and maintained or even improved treatment effectiveness compared to conventional MTD regimens. Importantly, lower dosing may actually enhance anti-tumor immunity through multiple mechanisms: reducing immunosuppressive cell populations, upregulating class I MHC expression (thereby facilitating T lymphocyte-mediated tumor cell recognition and destruction), killing cancer cells by what is called immunogenic cell death (ICD), which is known to activate dendritic cells, a key component of the immune system. Thus, coupling these approaches with ICIs may be particularly efficacious because it checks off multiple boxes in the cancer immunity cycle. In addition, low dose/metronomic chemotherapy inhibits angiogenesis, blood vessel formation necessary for tumor growth.
Dose alteration strategies include one or more of the following: dose reduction with more frequent dosing (metronomic), dose reduction without scheduling change, less frequent dosing, and innovative treatment sequencing approaches. These approaches will likely apply to chemotherapeutic drugs and ICIs. For example, there is accumulating data that AM administration of ICIs and their sequencing in relation to chemotherapy (e.g. delaying administration after chemotherapy as noted above) may impact outcomes dramatically (see Morningside Center blogs).
Yet one more approach to optimizing dosing and scheduling is to be guided by evolutionary biology principles. Cancer consistently evolves to develop resistance against therapeutic interventions, analogous to the way bacteria develop antibiotic resistance. The Morningside Center advocates for the application of fundamental evolutionary biology principles to predict and prevent the emergence of treatment resistance by strategically dose modulating, initiating, interrupting, or alternating treatments prior to clinical disease progression, similar to established approaches in agricultural pest management. These evolutionary-informed treatment strategies focus on adjusting therapeutic regimens based on simple, real-time biological assessments. This approach ensures that oncologists can adaptively modify therapy in a dynamic fashion, preventing or delaying resistance development.
One promising application of evolutionary principles to cancer treatment is known as adaptive therapy, which titrates treatment intensity based on tumor response rather than administering continuous maximum tolerated doses. Early clinical data in prostate cancer has demonstrated extended time to progression and reduced cumulative drug exposure, with corresponding reductions in toxicity and cost.
Collectively, all of these approaches align with the growing recognition that "more" is not always better in oncology and that thoughtfully designed, biologically-informed treatment schedules may optimize both outcomes and quality of life and reduce costs.