Precision in

Deborah Stephens, DO Lymphoma Research Foundation October 20, 2019 Overview •What is precision oncology? •What are genetic mutations? •What are examples of precision oncology in lymphoma? •What are future uses of precision oncology in lymphoma? What is Precision Oncology? •Diagnosis and treatment of cancer that customizes care based on genetics, proteins, environment, and lifestyle of the individual patient. •Tailor medical discussions, decisions, and products to a specific patient. •“Personalized Medicine” •“Targeted Treatments” •For example, choosing a specific cancer treatment based on the cancer’s genetic profile. What are Genes?

Short arm = P arm Tells the body DAD MOM what proteins to make DAD MOM Long arm = Q arm

https://cdn.prod-carehubs.net/n2/71b34990bba71dfd/uploads/2018/07/boldchromosomecellturquoise.png Provide body structure & What are Proteins? regulate body functions

https://cdn.prod-carehubs.net/n2/71b34990bba71dfd/uploads/2018/07/genemutations-aid.png What Types of Mutations are Possible?

https://www.4hcm.org/content.asp?contentid=185 Why Does Cancer Mutate Genes? •SURVIVAL! •Most mutations: • ↑ growth • ↑ multiplication • ↓ death •Example: • Double-hit Diffuse Large B-cell Lymphoma • #1 MYC gene rearrangement = ↑ growth • #2 BCL2 gene rearrangement = ↓ death • Combination = fast growing, lethal tumors!

https://biocare.net When Does Cancer Mutate Genes? •If my doctor tells me that my cancer has a genetic mutation, does this mean that I can pass this to my children? •Answer: Usually not for lymphoma •Germline mutations: • Come from sperm or egg • “Born with them” • Pass on to kids •Somatic mutations: • Happen from exposure or age, etc. • Not “born with them” • Not passed on to kids •Somatic mutations = common in lymphoma

https://cdn.prod-carehubs.net/n2/71b34990bba71dfd/uploads/2018/07/germline-vs-somatic3.png How is Precision Oncology Used in Lymphoma?

DIAGNOSIS PROGNOSIS TREATMENT

What kind of How bad is my What treatment lymphoma? lymphoma? will work best? How is Precision Oncology Used in Lymphoma?

https://www.nature.com/articles/modpathol201692/figures/1 Diagnosis •Some have specific markers that confirm diagnosis: • Example: • Translocation 11;14 (Genetic marker) MCL in Brown = + Stain for • Cyclin D1 (overproduced protein) under microsope Cyclin D1 protein

https://biocare.net/ Diagnosis •Some lymphomas have specific markers that confirm diagnosis: • Example: Waldenstrom’s macroglobulinemia • MYD88 L265P • Found in >90% of patients with WM

https://www.nature.com/articles/leu2013294 How is Precision Oncology Used in Lymphoma?

DIAGNOSIS PROGNOSIS

What kind of How bad is my lymphoma? lymphoma? Prognosis •Chronic Lymphocytic • Deletion of 17p (short arm) • Eliminates TP53 (important tumor suppressor) • Shorter survival • Poor response to treatment

https://www.researchgate.net/figure/Alterations-of-the-chromosomal-region-17p-in-DLBCL-a-Deletion-of-17p-arrow-detected_fig5_5865145 Prognosis •Diffuse Large B-cell Lymphoma •MYC/BCL2 rearrangements •“Double Hit Lymphoma” •Shorter survival •Poor response to treatment

https://biocare.net How is Precision Oncology Used in Lymphoma?

DIAGNOSIS PROGNOSIS TREATMENT

What kind of How bad is my What treatment lymphoma? lymphoma? will work best? Treatment •Goals of research in precision oncology: • Figure out how the cancer lives • Develop a drug to prevent TARGETEDCANCER the survival THERAPYCELLS • Better if your target is not in normal cells • = Targeted Therapy Treatment •Bruton tyrosine kinase (BTK) inhibitors • Ibrutinib, acalabrutinib •BTK required for cancer survival = the gas •BTK inhibitors block the survival signals •Approved drugs: • Ibrutinib = CLL, MCL, WM, MZL • Acalabrutinib = MCL BTK inhibitor •Drugs in clinical trials • Zanubrutinib • ARQ-531 • LOXO-305 Too much BTK • SNS-062 LYMPHOMA/ • Others CLL

https://www.123rf.com/stock-photo/fuel_gun.html Treatment •BCL2 inhibitor: Venetoclax •BCL2 protein overexpressed in CLL/lymphoma – prevents cancer cell death •Venetoclax blocks BCL2 and allows cancer cell death •Take your foot off the brake and drive car over a cliff

http://www.people.com/article/susan-sarandon-geena-davis-thelma-louise-women-film; http://theredlist.com/wiki-2-24-224-267-view-fiction-profile-thelma.html; http://pyxurz.blogspot.com/2011/08/thelma-louise-page-6-of-6.html; http://www.rogerebert.com/balder-and-dash/fade-to-white-thelma-and-louise-turns-25 Treatment •Histone Deactylase Inhibitors: HDAC •HDAC ↑ in tumor cells and ↓ tumor suppressor genes •HDAC inhibitors allow the tumor suppressor genes to work and kill the cancer cells •Approved HDAC inhibitors= • CTCL: vorinostat, romidepsin • PTCL: belinostat

http://www.cgxinc.com/en/img/contents_clinical32.gif Treatment •Immunotherapy = Using the and environment to fight lymphoma • Checkpoint inhibitors • Antibodies • CART cell therapy Therapy = Checkpoint Inhibitors

• PD-1 (on T-cells) = looks for PD-L1 on • PD-1 = Passport control other cells • PD-L1 = Passport – if valid, can access • Once PD-1 and PD-L1 are bound = and continue living in the country prevents T-cell killing • Tumor cells make fake passports • Tumor cells ↑ PD-L1 so they will not be killed by T-cells • Checkpoint inhibitors = border wall (don’t allow interaction of passport and • Blocking this interaction allows the passport control) tumor cells to be killed by the T-cells (and some normal cells) • Blocks admission of non-residents (and a lot of residents as well!) • Approved checkpoint inhibitors = nivolumab and pembrolizumab in Therapy = Antibodies

•Specifically targeting something that lives on the outside of a lymphoma/CLL cell

Antibodies (CD20): Antibody Attached to Chemo Drug: ◦ o Brentuximab (CD30): Hodgkin, ALCL ◦ Ofatumumab o Polatuzumab (CD79b): DLBCL ◦ Obinutuzumab Therapy = CART

IMMUNE SYSTEM

CANCER

CD19

CART Approved: Future: • Yescarta (CD19): DLBCL • Many additional targets • Kymriah (CD19): DLBCL being studied… Precision Oncology: In the Clinic •51 yo man with DLBCL •Relapsed after multiple treatments: • RCHOP, RICE, RGemOx •Transplant not an option •Sequenced tumor sample Precision Oncology: In the Clinic

Not perfect. Difficult to target every single mutation. Reserved for when there are no other options. Future of Precision Oncology in Lymphoma •Quicker sequencing •Deeper sequencing •Sequencing without a biopsy: circulating tumor DNA •Not treatment of “mantle cell lymphoma” but treatment of “TP53 mutated cancer?” •Prevention of lymphoma? Summary •What is precision oncology? •What are genetic mutations? •What are examples of precision oncology in lymphoma? •What are future uses of precision oncology in lymphoma? Thank You

Lymphoma Team: Patients and Families: • Drs. Glenn, Hu, Shah, Halwani • Without you, research is not possible • Natalie & Renee, CNP • You are truly paying it forward • Ashley Newland, PharmD • McKenna Burt, RN • Clinical Research/Data Coordinators