MYC-directed cancer treatment strategies – discovering the Achilles’ heel of cancer
The aim of MYCimmune program is to translate MYC-directed therapeutic approaches to benefit cancer patients. While most MYC-directed synthetic lethal (MYC SL) strategies are in the development stage, several strategies have already been advanced to the clinic. Building upon the SL discovered between MYC and CDK1 inhibition by the Goga Lab and colleagues at UCSF (Goga et al.), Drs. Jo Chien, Hope Rugo and colleagues at UCSF initiated a Phase Ib/II Trial to assess Dinaciclib (CDK1/2/5/9 inhibitor) with Pembrolizumab (anti-PD1) in metastatic TNBC; this is near completion (NCT01676753) with results presented at ASCO 2020 (Chien et al.). The results show that tumors with high MYC expression were significantly more likely to respond to this combination treatment, a first such trial to demonstrate MYC-selectivity in breast cancer treatments.
In Helsinki, the Klefström lab recently discovered that combination of venetoclax (BCL-2 inhibitor) + metformin (mitochondrial complex I inhibitor) together with PD-1 inhibitor can dramatically eliminate MYC-driven breast tumors in animal models (Haikala et al.). Building upon this finding, Dr. Johanna Mattson, MD, PhD at Helsinki University Hospital Comprehensive Cancer Center has developed a Phase Ib trial concept. This trial is unique in that one of the inclusion criteria includes MYC overexpression as a biomarker. The trial is being considered as an investigator-initiated study in Helsinki.
The portfolio of MYCImmune program also involves many other actionable and clinically viable synthetic-lethal strategies to selectively kill MYC overexpressing cells, some of them highlighted in the Development Pipeline.
MYCimmune program uses computational predictions, drug screens and hypothesis-driven approaches to discover new MYC-dependent cancer vulnerability pathways and drugs to be advanced to clinical testing. Top candidate hits will be rigorously validated through advanced ex vivo and in vivo cancer models before translational consideration. In these processes, we collaborate with academic, biotech and pharma partners. For collaborative opportunities, visit Innovation and partnering.
The MYCimmune project uses a variety of computational predictions and drug screening facilities at UCSF and the University of Helsinki to uncover MYC synthetic lethal drugs and cellular pathways. The graph below depicts 52 drugs in 23 biological subcategories, with potential for synthetic lethal action with MYC.
There are several cell pathways that have been discovered for their synthetic lethal activity in cancerous cells with high MYC expression, and which are currently being jointly tested in MYCimmune program for their utility in the scope of development of MYC guided therapies.
For our current MYC SL leads, Read More
Cell Cycle and Apoptosis
- AURKA/B (Yang et al. 2010., den Hollander et al.)
- BCL-2 family proteins (Haikala et al. 2019., Nieminen et al. 2013)
- CDK-1 (Horiuchi et al 2012, Lawson et al. 2015), LYN (Martins et al. 2015)
- PIM-1 (Horiuchi et al. 2016)
- AMPK (Nieminen et al. 2013, Haikala et al. 2019.)
- Fatty Acid Oxidase (Camarda et al. 2016, Camarda et al. 2018),
- Glutamine (GLN), Glutathione (GSH) (Anderton et al. 2017).
Transcription and Replication
We believe that the new MYC-directed synthetic lethal approaches will elicit improved efficacy across diverse tumor types (Pan-Can) in which MYC is overexpressed. Therefore, we are investigating MYC SL approaches in both selected cancer types, like breast cancer, and in a tumor agnostic setting.
Prolonging treatment responses by combining of MYC-directed synthetic-lethal therapies and immunotherapy
Immunotherapy is a type of cancer treatment that activates the body’s own immune system to prevent, control and eliminate cancer. The immunotherapy strategies include diverse therapeutic targets and treatment approaches including adoptive cell therapy, cancer vaccines, immunomodulators, oncolytic viruses and targeted therapies.
Recent collaborative work in the MYCimmune program has identified ways in which the MYC oncogene elicits tumor immune evasions, and how combination immune therapies can elicit prolonged tumor responses in MYC overexpressing tumors (Lee et al.)
The research focus of MYCimmune is to identify immunomodulator targets and therapeutic antibodies as these agents that can be readily combined with MYC-directed therapies to create treatment combination with prolonged responses for patients.
We have several different biologic rationales to support combination immunotherapy approaches. One is to substitute the toxic chemotherapy (CHT) component in the CHT-immunotherapy combination with more selective drugs, which induce synthetic lethality (SL) in the context of specific activated oncogene pathways. Such approaches would be expected to improve therapeutic efficacy while diminishing adverse effects for patients. Since the MYC-directed SL strategies take advantage of the inherent vulnerabilities of cancer cells caused by the very same oncogenes that drive their growth, it is anticipated that optimal synthetic-lethal treatment selectively kills cancer cells, leaving normal healthy cells unscathed.
MYCimmune project has also recently discovered that MYC causes cancer cell resistance to the immune system, a state called immunosuppression, and the study established a new clinically viable strategy to overcome this MYC caused immunosuppression (Joyce et al.). This approach presents a new way to turn MYC overexpressing “cold” tumors (which lack immune cell infiltration in tumors) into “hot” tumors, which have tumor infiltrated lymphocytes and can be treated with immunomodulatory therapies.
Our research has demonstrated the feasibility of the following immunotherapy agents as part of or to be administered in combinations with MYC-directed strategies for the treatment of cancer.