• Newly diagnosed pathologically-confirmed locally advanced rectal cancer (defined by 8th edition AJCC stage 2 or 3, or stage 1 not eligible for sphincter-sparing surgery) with plans to proceed with total neoadjuvant short course radiation as part of their neoadjuvant therapy as confirmed by treating physician

• At least 18 years of age.

• ECOG performance status 0, 1, or 2

• Adequate bone marrow and organ function as defined below:

‣ Absolute neutrophil count ≥ 1.5 K/cumm

⁃ Platelets ≥ 100 K/cumm

⁃ Hemoglobin \> 9 g/dL

⁃ Total bilirubin ≤ 1.5 x IULN

⁃ AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

⁃ Serum creatinine \< 1.5 x IULN OR measured or calculated creatinine clearance ≥ 50 mL/min/1.73 m2

• Applicable to subjects enrolled at Washington University and Dana Farber Cancer Institute only: Willing to undergo study-related biopsies subject to accessibility of tumor, appropriateness of biopsy (not contraindicated), and continued subject consent. If biopsy is not safe and feasible per treating physician, then patient may still enroll with permission of sponsor-investigator.

• Women of childbearing potential and men must agree to contraceptive methods as described in protocol prior to study entry, for the duration of study participation, and for 120 days after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

• Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).